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MX2014014482A - Amides of 2-amino-4-arylthiazole compounds and their salts. - Google Patents

Amides of 2-amino-4-arylthiazole compounds and their salts.

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Publication number
MX2014014482A
MX2014014482A MX2014014482A MX2014014482A MX2014014482A MX 2014014482 A MX2014014482 A MX 2014014482A MX 2014014482 A MX2014014482 A MX 2014014482A MX 2014014482 A MX2014014482 A MX 2014014482A MX 2014014482 A MX2014014482 A MX 2014014482A
Authority
MX
Mexico
Prior art keywords
formula
compound
trifluoromethyl
phenyl
dimethyl
Prior art date
Application number
MX2014014482A
Other languages
Spanish (es)
Other versions
MX354014B (en
Inventor
Abraham Thomas
Sukeerthi Kumar
Suresh Mahadev Kadam
Sukumar Sinha
Bipin Parsottam Kansagra
Sachin Gavhane
Sandeep Bandu Khandagale
Shailesh Pawase
Jayant Prakashrao Patil
Shailendra Bhadane
Bhavna Mishra
Rajesh Dwivedi
Original Assignee
Glenmark Pharmaceuticals Sa
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Publication date
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=54193746&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=MX2014014482(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Glenmark Pharmaceuticals Sa filed Critical Glenmark Pharmaceuticals Sa
Publication of MX2014014482A publication Critical patent/MX2014014482A/en
Publication of MX354014B publication Critical patent/MX354014B/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present disclosure is directed to salts of N-{4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4- dioxo-1,2,3,4- tetrahydrothieno[2,3- d]pyrimidin-5-yl)acetamide and process for the preparation thereof (formula II).

Description

AMIDAS OF COMPOUNDS OF 2-AMINO-4-ARILTIAZOL AND ITS SALTS FIELD OF THE INVENTION The present application relates to salts of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide and to the process for the preparation thereof.
BACKGROUND OF THE INVENTION It is believed that the transient ankyntric potential receptor (TRPA1) is expressed in nociceptive neurons. Nociceptive neurons of the nervous system detect peripheral damage and transmit pain signals. TRPA1 is bound to the membrane and most likely acts as a channel regulated by heterodimeric voltage. It is believed to have a particular secondary structure, its end / V-terminal is aligned with a large number of ankyrin repeats that are believed to form a structure similar to a spring. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures (activated at 17 ° C), spicy natural compounds (eg mustard, cinnamon and garlic) and environmental irritants (MacPherson LJ et al, N ature, 2007, 445; 541-545). Harmful compounds activate TRPA1 ion channels through the covalent modification of cisterns to form bound adducts covalently The variety of endogenous molecules produced during tissue injury / inflammation as pathological activators of the TRPA1 receptor has been identified. These include hydrogen peroxide which is produced due to oxidative stress generated during the inflammation, alkenyl aldehyde 4-HNE, an intracellular lipid peroxidation product and the cyclopentenone prostaglandin 15dPGJ2 which is produced from PGD2 during the inflammation / allergic response. TRPA1 is also activated in a receptor-dependent manner by bradykinin (BK) that is released during tissue injury in peripheral terminals.
International PCT publication number WO 2010/109334 discloses thieno-pyrimidinedione compounds of formula (I) which are shown to have TRPA1 inhibition activity. Therefore, the compounds of formula (I) may be useful for the treatment of diseases, conditions and / or disorders modulated by TRPA1.
OR) in which, R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl; R4, R5, R6, R7, R8 and R9, which may be the same or different, are each independently selected from the group comprising hydrogen, halogen, cyano, hydroxyl, nitro, amino, alkyl (Ci-C6), alkoxy (Ci -C6), haloalkyl (C! -Ce), haloalkoxy (Ci-C6), cycloalkyl (C3-C6), cycloalkyl (C3-C6) -alkyl (C1-C6) and cycloalkyl (C3-C6) -alcoxyl (CrC6) ).
The A / - was described. { 4- [2,4-d.fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-] pyrimidin-5-yl) acetamide, hereinafter referred to as "compound of formula (II) ", and its use for the treatment of disorders mediated by TRPA1 in the international publication number WO 2010/109334.
In the formulation of pharmacological compositions, it is important that the pharmaceutical active ingredient be in a form that can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of the further manufacture of pharmaceutical formulations comprising the active pharmaceutical ingredient. The development of drugs therefore involves research relating to finding pharmaceutically acceptable salt forms of a drug. It may also be desirable to examine various polymorphs of these salts, which have better handling properties as well as can also show improved physicochemical and pharmacokinetic and pharmacodynamic properties.
In addition, the development of a commercial drug candidate involves many steps, such as the development of a cost-effective synthesis method that is effective in the large-scale manufacturing process.
SUMMARY OF THE INVENTION The present application relates to salts of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c] pyrimidin-5-yl) acetannide represented by the formula (II) and to the process for preparing them.
/ N / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c /] pinmidin-5-yl) acetamide, hereinafter referred to as "compound" of formula (II) ".
In one embodiment, the present invention relates to the potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-cf] pyrimidin-5-yl) acetamide.
In another embodiment, the present invention relates to the salt of potassium of / \ / -. { 4- [2,4-difluoro-3- (trifluoromethyl) † enyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide in crystalline form.
In yet another embodiment, the potassium salt of a compound of formula (II) is provided in amorphous form.
In yet another embodiment, the solid state forms of the potassium salt of a compound of formula (II) exist in an anhydrous and / or solvent free form or as a hydrate and / or solvate form.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a solid state form of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the solid state form of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In yet another embodiment, there is provided a method for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the crystalline potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In one embodiment, the potassium salt of a compound of formula (II) having a water content of less than about In another embodiment, the crystalline potassium salt of a compound of formula (II) having a water content of less than about 5% is provided.
In another embodiment, the potassium salt of the compound of formula (II) having a water content of about 0.2-2.0% is provided as determined by the Karl Fischer method.
In another embodiment, the potassium salt of the compound of formula (II) having a water content in the range of 0.2 to 1.0% as determined by the Karl Fischer method is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having a water content of about 0.2-2.0% as determined by the Karl Fischer method is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having a water content in the range of 0.2 to 1.0% is provided as determined by the Karl Fischer method.
In another embodiment, the potassium salt of the compound of formula (II) which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 16.0% in 48 hours at 25 ° is provided. C / relative humidity (RH) of 90%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 16.0% in 48 hours at 25 ° C / relative humidity (RH) of 90%.
In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 6.6% in 48 hours at 25 ° is provided. C / HR of 80%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 6.6% in 48 hours to 25 hours. ° C / HR of 80%.
In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 3.5% in 48 hours at 25 ° is provided. C / HR of 60%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 3.5% in 48 hours at 25 hours. ° C / HR of 60%.
In another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range from about 1 pm to about 100 pm.
In yet another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 50 pm is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 20 pm is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 100 pm is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 50 pm is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 20 pm is provided.
In another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.3 m? Ti to about 10 m? h.
In yet another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.5 mm to about 8 pm is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.5 μm to about 5 mm is provided. .
In another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.3 mhh to about 10 mhh is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (Di0) having a size in the range of from about 0.5 mhh to about 8 m is provided? you.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (Di0) having a size in the range of from about 0.5 m? ti to about 5 mhi.
In another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 4 mIi to about 300 m? H is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 5 μm to about 250 mhh is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 5 mhh to about 200 mlli is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 5 mhh to about 150 mhh is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 4 mlh to about 300 mhh.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 5 mhh to about 250 μm is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (Dg0) having a size in the range of from about 5 pm to about 200 pm is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (Dgo) having a size in the range of from about 5 μm to about 150 μm is provided.
In another embodiment, the present invention also relates to the substantially pure potassium salt of the compound of formula (II). For the purposes of this invention, substantially pure is more than about 90% pure.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 95%.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 98%.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 99%.
In yet another embodiment, the present invention also relates to the substantially pure crystalline potassium salt of the compound of formula (II). For the purposes of this invention, substantially pure is more than about 90% pure.
In yet another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 95%.
In yet another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 98%.
In still another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 99%.
In another embodiment, the present invention relates to the crystalline potassium salt of the compound of formula (II) and to the process for the preparation thereof.
In yet another embodiment, the present invention relates to the crystalline potassium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the process for preparing the crystalline form of the potassium salt of the compound of formula (II).
In another embodiment, the present invention relates to the crystalline form of the potassium salt of the compound of formula (II) which is designated form I.
In yet another embodiment, the present invention relates to the process for preparing the crystalline form of the potassium salt of the compound of formula (II) which is designated form I.
In another embodiment, the present invention relates to the crystalline form of the potassium salt of the compound of formula (II) which is designated form II.
In yet another embodiment, the present invention relates to the process for the preparation of the crystalline form of the potassium salt of the compound of formula (II) designated form II.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering form I of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising form I of the potassium salt of the compound of formula (II) together with excipients pharmaceutically acceptable In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering form II of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising form II of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to the amorphous potassium salt of the compound of formula (II) and to the process for the preparation thereof.
In yet another embodiment, the present invention relates to the amorphous potassium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the process for the preparation of amorphous potassium salt of the compound of formula (II).
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the amorphous form of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the amorphous form of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to the sodium salt Crystalline of the compound of formula (II) which is designated form A and to the process for the preparation thereof.
In yet another embodiment, the present invention relates to the crystalline sodium salt of the compound of formula (II) which is designated form A.
In yet another embodiment, the present invention relates to the process for the preparation of the crystalline sodium salt of the compound of formula (II) which is designated form A.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the crystalline form A of the sodium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline form A of the sodium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to the amorphous sodium salt of compound of formula (II) and to the process for the preparation thereof.
In another embodiment, the present invention relates to the amorphous sodium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the process for the preparation of the amorphous sodium salt of the compound of formula (II).
In another embodiment, a method for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the amorphous sodium salt of the compound of formula (II), or a pharmaceutical composition comprising the amorphous sodium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to the lithium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the process for the preparation of the lithium salt of the compound of formula (II).
In another embodiment, the present invention relates to the crystalline lithium salt of the compound of formula (II) which can be designated alpha form and to the process for the preparation thereof.
In another embodiment, the present invention relates to the crystalline lithium salt of the compound of formula (II) which can be designated alpha form.
In yet another embodiment, the present invention relates to the process for the preparation of the crystalline lithium salt of the compound of formula (II) which can be designated alpha form.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the lithium salt of the compound of formula (II), or a pharmaceutical composition comprising the lithium salt of the compound of Formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the crystalline lithium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline lithium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
The present application also relates to the crystalline forms of N-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated compound of formula (II) and to the process for preparing them.
In another embodiment, the crystalline forms of the compound of formula (II) exist in an anhydrous and / or solvent-free form or as a hydrate and / or solvate form.
In yet another embodiment, a crystalline form of the compound of formula (II) designated form X is provided.
In yet another embodiment, there is provided a process for the preparation of the crystalline form of the compound of formula (II) designated Form X.
In yet another embodiment, a crystalline form of the compound of formula (II) designated Y-form is provided.
In yet another embodiment, there is provided a process for the preparation of the crystalline form of the compound of formula (II) designated Y form.
In yet another embodiment, a crystalline form of the compound of formula (II), designated Z-form, is provided.
In yet another embodiment, there is provided a process for the preparation of the crystalline form of the compound of formula (II) designated Z-form.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the Y form of the compound of formula (II), or a pharmaceutical composition comprising the Y form of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the Z form of the compound of formula (II), or a pharmaceutical composition comprising the Z form of the compound of formula (II) together with pharmaceutically acceptable excipients.
In yet another embodiment, a compound of formula (II) is provided crystalline having a water content of less than about 5%.
In yet another embodiment, a crystalline formula (II) compound having a water content of about 0.2-2.0% as determined by the Karl Fischer method is provided.
In yet another embodiment, a crystalline formula (II) compound having a water content in the range of 0.2 to 1.0% as determined by the Karl Fischer method is provided.
In another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 100 mhh, or preferably less than 50 mhh, or more preferably less than 20 mhh is provided.
In another embodiment, a crystalline formula (II) compound having an average particle size (D50) less than 100 mhi is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 50 mhh is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D5o) of less than 20 mhh is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 10 mhh is provided.
In another embodiment, the crystalline compound of formula (II) has about 10% of the particles (D10) having a size of less than 10 mlh, or preferably less than 5 mhh.
In yet another embodiment, the crystalline compound of formula (II) has about 10% of the particles (Di0) having a size of less than 10 mhi.
In yet another embodiment, the crystalline compound of formula (II) has about 10% of the particles (Dio) which are smaller than 5 mhh.
In another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 200 μm, or preferably less than 100 mhi, or more preferably less than 50 mhh.
In yet another embodiment, the crystalline compound of formula (II) has approximately 90% of the particles (D90) having less than 200 mhh.
In yet another embodiment, the crystalline compound of formula (II) has approximately 90% of the particles (D90) having less than 100 mhh.
In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 50 mhi.
In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 20 mhp.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 50 m2 / gm, preferably less than 25 m2 / gm or more preferably less than 10 m2 / gm is provided.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 50 m2 / gm is provided.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 25 m2 / gm is provided.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 10 m2 / gm is provided.
The present invention also relates to the process for the preparation of the thieno-pyrimidinedione compound of formula (II).
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the powder X-ray diffraction pattern of the crystalline potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated form I.
Figure 2 is the infrared (IR) spectrum of the crystalline potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothione [2,3-cf] pyrimidin-5-yl) acetamide designated form I.
Figure 3 is the powder X-ray diffraction pattern of the crystalline potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated form II.
Figure 4 is the infrared (IR) spectrum of the crystalline potassium salt of A / - (4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl.} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide designated form II.
Figure 5 is the X-ray diffraction pattern of amorphous potassium salt powder of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1S-dimethyl ^^ - dioxo-I ^. S ^ -tetrahydrothieno ^ .S-c / jpyrimidin-S-i acetamide.
Figure 6 is the powder X-ray diffraction pattern of the crystalline sodium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated form A.
Figure 7 is the infrared (IR) spectrum of the crystalline sodium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide designated form A.
Figure 8 is the powder X-ray diffraction pattern of the amorphous sodium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-d-oxo-1,2,3,4-tetrahydro-thieno [2,3-c] pyrimidin-5-yl) acetamide.
Figure 9 is the infrared (IR) spectrum of the amorphous sodium salt of / V- (4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl.} -2- (1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c (] pyridin-5-yl) acetamide.
Figure 10 is the powder X-ray diffraction pattern of the salt of crystalline lithium of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated alpha form.
Figure 11 is the infrared (IR) spectrum of the crystalline lithium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated alpha form.
Figure 12 is the powder X-ray diffraction pattern of N-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-jpyrimidin-5-yl) acetamidada crystalline designated form X.
Figure 13 is the infrared (IR) spectrum of / V-. { 4- [2,4-d.fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-] pyrimidin-5-yl) acetamide crystalline designated form X.
Figure 14 is the powder X-ray diffraction pattern of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c / lpyrimidin-5-yl) crystalline acetamide designated Y form.
Figure 15 is the infrared (IR) spectrum of A / ^ - ^^ - difluoro-S- (trifluoromethyl) phenylj-l, 3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide crystalline designated Y form.
Figure 16 is the powder X-ray diffraction pattern of N-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothione [2,3-d] pyrinnidin-5-yl) crystalline acetamide designated Z-form.
Figure 17 is the infrared (IR) spectrum of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide crystalline designated Z form.
DETAILED DESCRIPTION OF THE INVENTION The present application relates to salts of A / -. { 4- [2, 4-d if luoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c] pyrimidin-5-yl) acetamide designated compound of formula (II) and to the process for preparing them.
In one embodiment, the present invention relates to the potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno [2,3-c] pyrimidin-5-yl) acetamide.
In another embodiment, the present invention relates to the potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-cf] pyrimidin-5-yl) acetamide in crystalline form.
In yet another embodiment, the potassium salt of a compound of formula (II) is provided in an amorphous form.
In yet another embodiment, the solid state forms of the potassium salt of a compound of formula (II) exist in an anhydrous and / or solvent free form or as a hydrate and / or solvate form.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a solid state form of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the solid state form of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In yet another embodiment, there is provided a method for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the crystalline potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In one embodiment, the potassium salt of a compound of formula (II) having a water content of less than about 5%.
In another embodiment, the crystalline potassium salt of a compound of formula (II) having a water content of less than about 5%.
In another embodiment, the potassium salt of the compound of formula (II) having a water content of about 0.2-2.0% is provided as determined by the Karl Fischer method, more preferably in the range from 0.2 to 1, 0%.
In another embodiment, the potassium salt of the compound of formula (II) having a water content of about 0.2-2.0% is provided as determined by the Karl Fischer method.
In another embodiment, the potassium salt of the compound of formula (II) having a water content in the range of 0.2 to 1.0% as determined by the Karl Fischer method is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having a water content of about 0.2-2.0% as determined by the Karl Fischer method is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having a water content in the range of 0.2 to 1.0% is provided as determined by the Karl Fischer method.
In another embodiment, the potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 16.0% in 48 hours at 25 ° C / relative humidity (RH) of 90%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 16.0% in 48 hours to 25 hours. ° C / relative humidity (RH) of the 90% In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 6.6% in 48 hours at 25 ° is provided. C / HR of 80%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 6.6% in 48 hours to 25 hours. ° C / HR of 80%.
In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 3.5% in 48 hours at 25 ° is provided. C / HR of 60%.
In another embodiment, the crystalline potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of about 0.80% to about 3.5% in 48 hours at 25 hours. ° C / HR of 60%.
In another embodiment, the potassium salt of the compound of formula (II) having an increase in moisture content of about 15.2% or less when stored at a relative humidity of 90% at a temperature of 25 ° is provided. C for 48 h.
In another embodiment, the potassium salt of the compound of formula (II) having an increase in moisture content of about 5.8% or less when stored at a relative humidity of 80% at a temperature of 25 ° is provided. C for 48 h.
In another embodiment, the potassium salt of the compound of formula (II) having an increase in moisture content of about 2.7% or less when stored at a relative humidity of 60% at a temperature of 25 ° is provided. C for 48 h.
In another embodiment, the potassium salt of the compound of formula (II) is provided which exhibits the gradual increase in moisture content from the initial value of 0.80% to 16.0% in 48 h at 25 ° C / relative humidity (HR) of 90%.
In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of 0.80% to 6.6% in 48 h at 25 ° C / RH is provided. 80% In another embodiment, the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of 0.80% to 3.5% in 48 h at 25 ° C / RH is provided. 60% In another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 mm to about 100 mhh, or from about 1 miti to about 50 miti or from approximately 1 mhh to approximately 20 mhh.
In another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D5o) in the range of from about 1 pm to about 100 miti is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 mhi to about 50 mGP is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 pm to about 20 mhh is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 mhh to about 100 miti is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 mhh to about 50 mGTI.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having an average particle size (D50) in the range of from about 1 mhh to about 20 mhh is provided.
In another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.3 m? Ti to about 10 mhi is provided, or from about 0.5 μm to about 8 mhh, preferably from about 0.5 mhi to about 5 μm.
In another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (Di0) having a size in the range of from about 0.3 mhh to about 10 mhh is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.5 μm to about 8 mhh is provided. .
In yet another embodiment, the potassium salt of the compound of formula (II) having about 10% of the particles (D-i0) having a size in the range of from about 0.5 mhh to about 5 pm is provided. .
In another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.3 mhh to about 10 μm is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (Dio) having a size in the range of from about 0.5 μm to about 8 mhh is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having about 10% of the particles (D10) having a size in the range of from about 0.5 μm to about 5 mii is provided.
In another embodiment, the potassium salt of the compound of formula (II) having about 90% of the particles (Dgo) having a size in the range of from about 4 pm to about 300 pm or from about 5 pm to about 250 pm, preferably from about 5 pm to about 200 mhh, and more preferably from 5 mhz to about 150 mhh.
In another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 4 mm to about 300 miti is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 5 mlti to about 250 mhi is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 5 mhi to about 200 mhh is provided.
In yet another embodiment, the potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 5 mhh to about 150 mhh is provided.
In another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from approximately 4 mhh to approximately 300 mhh.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 5 μm to about 250 mhh is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having about 90% of the particles (D90) having a size in the range of from about 5 mhi to about 200 mhi is provided.
In yet another embodiment, the crystalline potassium salt of the compound of formula (II) having approximately 90% of the particles (D90) having a size in the range of from about 5 μm to about 150 mhh is provided.
In Table 1, the particle size characteristics for the potassium salt of the compound of formula (II) are given for some of the batches.
Table 1: In another embodiment, the present invention also relates to the substantially pure potassium salt of the compound of formula (II). For the purposes of this invention, substantially pure is more than about 90% pure.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 95%.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 98%.
In yet another embodiment, the present invention relates to the substantially pure potassium salt of the compound of formula (II) having a purity greater than about 99%.
In yet another embodiment, the present invention also relates to the substantially pure crystalline potassium salt of the compound of formula (II). For the purposes of this invention, substantially pure is more than about 90% pure.
In yet another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 95%.
In yet another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 98%.
In still another embodiment, the present invention relates to the substantially pure crystalline potassium salt of the compound of formula (II) having a purity greater than about 99%.
In another embodiment, the present invention relates to the crystalline potassium salt of the compound of formula (II) and to the process for preparation of it.
In yet another embodiment, the present invention relates to the crystalline potassium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the crystalline form of the potassium salt of the compound of formula (II) which is designated form I.
In yet another embodiment, form I is characterized by the powder X-ray diffraction pattern (XRPD) as shown in Figure 1.
In yet another embodiment, form I is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 20: 15.93, 20.61, 23.63, 24.47 and 25.08 ± 0.2.
In yet another embodiment, form I is further characterized by the characteristic X-ray diffraction pattern comprising the next peak expressed in terms of 20: 23.63 + 0.2.
In yet another embodiment, form I is further characterized by the characteristic X-ray diffraction pattern comprising the next peak expressed in terms of 20: 24.47 ± 0.2.
In yet another embodiment, form I is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 20: 23.63 and 24.47 ± 0.2.
In yet another embodiment, the form I is further characterized by the peaks of the characteristic X-ray diffraction pattern expressed in terms of 2Q as presented in table 2.
Table 2: Two prominent theta positions and relative intensities of XRPD of Form I In yet another embodiment, form I is characterized by the Fourier Transform Infrared Spectroscopy (FT-IR) pattern as shown in Figure 2.
In another embodiment, the present invention relates to another crystalline form of the potassium salt of the compound of formula (II) which is designated form II.
In yet another embodiment, form II is characterized by the powder X-ray diffraction pattern (XRPD) as shown in Figure 3.
In yet another embodiment, the form II is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 12.07, 12.39, 20.98, 24.01 and 25.69 ± 0.2.
In yet another embodiment, the form II is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 24.01 and 25.69 ± 0.2.
In yet another embodiment, the form II is further characterized by the characteristic X-ray diffraction pattern comprising the following peak expressed in terms of 2Q: 24.01 ± 0.2.
In yet another embodiment, form II is further characterized by the characteristic X-ray diffraction pattern comprising the following peak expressed in terms of 2Q: 25.69 ± 0.2.
In yet another embodiment, the form II is further characterized by the peaks of the characteristic X-ray diffraction pattern expressed in terms of 2Q as presented in Table 3.
Table 3: Two prominent theta positions and relative intensities of XRPD of Form II In yet another embodiment, form II is characterized by the IR pattern as shown in Figure 4.
In another embodiment, the present invention relates to the amorphous potassium salt of the compound of formula (II).
In yet another embodiment, the amorphous form of the potassium salt of the compound of formula (II) is characterized by the powder X-ray diffraction pattern as shown in Figure 5.
In one embodiment, the present invention relates to the crystalline sodium salt of the compound of formula (II).
In another embodiment, the present invention relates to the crystalline sodium salt of the compound of formula (II) which is designated form A.
In yet another embodiment, form A is characterized by the powder X-ray diffraction pattern as shown in Figure 6.
In yet another embodiment, form A is further characterized by characteristic powder X-ray diffraction pattern peaks expressed in terms of 2Q as presented in table 4.
Table 4: Two prominent theta positions and relative intensities of XRPD of Form A In yet another embodiment, Form A is characterized by the IR pattern as shown in Figure 7.
In another embodiment, the present invention relates to the amorphous sodium salt of the compound of formula (II).
In yet another embodiment, the amorphous form of the sodium salt of the compound of formula (II) is characterized by the powder X-ray diffraction pattern as shown in Figure 8.
In yet another embodiment, the amorphous form of the sodium salt of the compound of formula (II) is characterized by the IR pattern shown in Figure 9.
In another embodiment, the present invention relates to the lithium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the crystalline lithium salt of the compound of formula (II).
In yet another embodiment, the present invention relates to the crystalline lithium salt of the compound of formula (II) which can be designated alpha form.
In yet another embodiment, the alpha form is characterized by the powder X-ray diffraction pattern as shown in Figure 10.
In yet another embodiment, the alpha form is characterized by the IR pattern shown in Figure 11.
In yet another embodiment, the alpha form is further characterized by the peaks of the characteristic X-ray diffraction pattern expressed in terms of 2Q as presented in Table 5.
Table 5: Two prominent theta positions and relative intensities of XRPD of the alpha form In one embodiment, the present invention relates to the process for the preparation of the potassium salt of the compound of formula (II), which comprises the following steps: (a) providing a solution or suspension of the compound of formula (II) in a suitable solvent or mixture of solvents; (b) adding a source of potassium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the source of potassium cation; Y (c) isolate the desired salt.
Step (a) involves providing a solution or suspension of the compound of formula (II) in a suitable solvent or solvent mixture. The solution or suspension of the compound of formula (II) can be obtained by dissolving or suspending the compound of formula (II) in a solvent or a mixture of solvents, or it can be obtained in situ, directly from the reaction in which it is formed the compound of formula (II). The suitable solvent can be any solvent that has no adverse effect on the reaction or on the reactants involved and able to dissolve the compound of formula (II), at least to some extent. The solvent system is preferably selected so as to facilitate salt formation. The solvent (s) that can be used to dissolve or suspend the compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol, n-propanol and tert-butanol; ketones, such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane and chloroform; hydrocarbons such as n-hexane, heptane, n-pentane, cyclopentane and cyclohexane; or any mixture thereof. The preferred solvent may include ethanol or n-pentane or combination thereof.
In step (b), the compound of formula (II) in solution or suspension is treated with a source of potassium cation. The potassium cation source can be potassium alkoxide such as potassium tert-butoxide or potassium ethoxide.
In one embodiment, the compound of formula (II) can be treated with potassium tert-butoxide brought to a suitable solvent such as alcohol. In one embodiment, the reaction can be carried out at a temperature ranging from about -5 ° C to about the boiling point of the solvent (s). In one embodiment, the reaction can be carried out at approximately -5 ° C to 0 ° C. The time required to complete the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent employed. However, as long as the reaction is carried out under the conditions set forth above, a period of from about 1 hour to about 24 hours or longer is sufficient.
Step (c) involves the isolation of the desired salt. The potassium salt of the compound of formula (II) produced in the reaction can be isolated using techniques including precipitation and / or decanting, filtration by gravity or suction, centrifugation or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. In another embodiment, the washing is with the solvent used in the above reaction. Alternatively, the solid obtained can optionally be washed with a suitable solvent such as acetonitrile or diethyl ether. The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the product is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, you can vary between about 1 and about 10 hours or longer.
In another aspect, the present invention relates to the process for the preparation of the crystalline potassium salt of the compound of formula (II) which is designated form I.
The process comprises bringing the compound of formula (II) to a mixture of ethanol and n-pentane, preferably in an inert atmosphere. The reaction mass can be cooled to about -5 to 0 ° C and stirred for about 10 minutes. To the reaction mass, an ethanolic solution of potassium tert-butoxide or potassium ethoxide may be added. The reaction mass can be further stirred at about -5 to 0 ° C for about one hour. To the reaction mixture, n-pentane can be added and the reaction mixture can be further stirred at room temperature for a suitable period of time such as for 1-2 h. The solid can be collected by methods including decanting, centrifugation, filtration by gravity, filtration by suction, or any other technique for the recovery of solids. The solid obtained further be brought to acetonitrile and the whole mass can be stirred at room temperature for a suitable period of time such as for 1-2 h. The solid can be collected by methods including decanting, centrifugation, gravity filtration, suction filtration, or any other technique for solid recovery. In a preferred embodiment, the solid can be filtered and washed with acetonitrile.
The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the potassium salt of the compound of formula (II) is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
In another embodiment, the present invention relates to another process for the preparation of the crystalline potassium salt of the compound of formula (II) designated form I, which process involves bringing the amorphous form of the potassium salt of the compound of formula (II) ) to acetonitrile; stir the reaction mass for a suitable period of time and isolate the crystalline form I. In this embodiment, the mixture of the amorphous form of the potassium salt of the compound of formula (II) and acetonitrile can be stirred for a period such as 1-2 hours at a suitable temperature such as 25-35 ° C. The solid can be collected by known techniques such as filtration. The solid obtained can be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example, the solid can be dried for 3-4 hours at 30-35 ° C under vacuum.
In a further embodiment, the present invention relates to the process for the preparation of the crystalline form of the potassium salt of the compound of formula (II) designated form II, which process comprises bringing the compound of formula (II) into a mixture of tert-butanol and n-pentane, preferably in an inert atmosphere. The reaction mass can be cooled to about -5 to 0 ° C and stirred for about 10 minutes. To the reaction mass, potassium tert-butoxide in tert-butanol may be added. The reaction mass can be further stirred at about -5 to 0 ° C for about one hour. The solid can be collected by methods including decanting, centrifugation, filtration by gravity, filtration by suction, or any other technique for the recovery of solids. The solid can also be washed with n-pentane. The solid obtained further be brought to acetonitrile and the whole mass can be stirred at room temperature for a suitable period of time such as for 1-2 h. The solid can be collected by methods including decanting, centrifugation, gravity filtration, suction filtration, or any other technique for solid recovery. In a preferred embodiment, the solid can be filtered and washed with acetonitrile.
The recovered solid may optionally be dried further.
The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or similar. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the potassium salt of the compound of formula (II) is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
In one embodiment, the present application also provides a process for the preparation of an amorphous form of the potassium salt of the compound of formula (II) which comprises heating the potassium salt of the compound of formula (II) on a heating mantle at 300 -320 ° C. The heating can be carried out at a reduced pressure.
In one aspect, the present invention relates to the process for the preparation of the sodium salt of the compound of formula (II), which comprises the following steps: (a) providing a solution or suspension of the compound of formula (II) in a suitable solvent or solvent mixture; (b) adding a source of sodium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the source of sodium cation; Y (c) isolate the desired salt.
Step (a) involves providing a solution or suspension of the compound of formula (II) in a solvent or a mixture of solvents suitable. The solution or suspension of the compound of formula (II) can be obtained by dissolving or suspending the compound of formula (II) in a solvent or a mixture of solvents, or can be obtained in situ, directly from the reaction in which the compound of formula (II) is formed. The suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and which can dissolve the compound of formula (II), at least to some extent. The solvent system is preferably selected so as to facilitate salt formation. The solvent (s) that can be used to dissolve or suspend the compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol and n-propanol; ketones, such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane and chloroform; hydrocarbons such as n-hexane, heptane, n-pentane, cyclopentane and cyclohexane; or any mixture thereof. The preferred solvent is ethanol.
In step (b), the compound of formula (II) in solution or suspension is treated with a source of sodium cation. The sodium cation source can be selected from sodium methoxide, sodium ethoxide and tertiary sodium butoxide. In one embodiment, the reaction can be carried out at a temperature ranging from about -5 ° C to about the boiling point of the solvent (s). In one embodiment, the reaction can be carried out at about -5 ° C to 0 ° C. The time required to complete the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent employed. However, as long as the reaction is carried out under the conditions set forth above, a period of from about 1 hour to about 24 hours or longer is sufficient.
Step (c) involves the isolation of the desired salt. The sodium salt of the compound of formula (II) produced in the reaction can be isolated using techniques such as decanting, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent or a mixture. of solvents.
The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the product is not degraded. The drying can be carried out for any desired time until the required purity is achieved.
For example, it may vary between about 1 and about 10 hours or longer.
In another aspect, the present invention relates to the process for the preparation of the crystalline sodium salt of the compound of formula (II) designated form A.
In a preferred embodiment, the compound of formula (II) can be carried to ethanol, preferably absolute ethanol, preferably in an inert atmosphere. The reaction mass can be cooled to a temperature of -5 to 0 ° C. To the reaction mass, an ethanolic solution of sodium methoxide can be added. Preferably, the addition can be carried out at the temperature of -5 to 0 ° C and the reaction mass can be maintained at that temperature for about one hour. The solid can be collected by various techniques. Isolation of the solid can be effected by methods including solvent removal, concentration of the reaction mass, or any other suitable technique.
Suitable techniques that can be used for solvent removal include and are not limited to rotational distillation using a device, such as, for example, a Buchi® Rotavapor® apparatus. In one embodiment, the solvent can be removed under reduced pressure.
The recovered solid may optionally be dried further.
The dried solid can be further stirred with acetonitrile for a period of 1 to 2 hours. The solid can be collected by known techniques such as as filtration, centrifugation or decanting.
The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at reduced pressure at suitable temperatures as long as the quality of the sodium salt of the compound of formula (II) is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
In another embodiment, the present invention relates to another process for the preparation of the crystalline sodium salt of the compound of formula (II) designated form A, which process involves carrying the amorphous form of the sodium salt of the compound of formula (II) ) to acetonitrile; stirring the reaction mass for a suitable period of time and isolating the crystalline form A. In this embodiment, the mixture of the amorphous form of the sodium salt of the compound of formula (II) and acetonitrile can be stirred for a period such as 1 -2 hours at a suitable temperature such as 25-35 ° C. The solid can be collected by known techniques such as filtration. The solid obtained can be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example, the solid can be dried for 3-4 hours at 30-35 ° C to empty.
In one embodiment, the present application provides a process for the preparation of an amorphous form of the sodium salt of the compound of formula (II), which comprises: (a) providing solution or suspension of the sodium salt of the compound of formula (II) in a solvent or a mixture of solvents; Y (b) isolating an amorphous form of the sodium salt of the compound of formula (II).
In a preferred embodiment, the compound of formula (II) can be carried to an alcohol for example, to ethanol and an ethanolic solution of sodium tert-butoxide can be added at an appropriate temperature. For example, the addition can be carried out in a temperature range of -5 to 0 ° C. The reaction mixture can be stirred at -5 to 0 ° C for about 1 h.
Step b) involves the isolation of an amorphous form of the sodium salt of the compound of formula (II).
In a preferred embodiment, the isolation step (b) can be carried out by removing solvent. Suitable techniques that can be used for solvent removal include using a rotational distillation device such as a Buchi® Rotavapor® apparatus, spray drying, thin-film and agitated drying, freeze-drying (lyophilization), or any other suitable technique .
The solvent can be removed, optionally under reduced pressure, at temperatures below about 60 ° C, below about 40 ° C, below about 20 ° C, or any other suitable temperature.
The compound obtained from step (b) can be collected using techniques such as by scraping, or other techniques specific to the equipment used.
The product thus isolated may optionally be further dried to provide an amorphous form of the sodium salt of the compound of formula (II). The drying can be carried out in a suitable manner in a tray dryer, vacuum oven, Buchi® Rotavapor® apparatus, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressure at suitable temperatures. The drying can be carried out for any period of time required to obtain a desired quality, such as from about 15 minutes to several hours.
In one aspect, the present invention relates to the process for the preparation of the lithium salt of the compound of formula (II) comprising the following steps: (a) providing a solution or suspension of the compound of formula (II) in a suitable solvent or solvent mixture; (b) add a source of lithium cation to the solution or suspension of step (a) or adding the solution or suspension of step (a) to the lithium cation source; Y (c) isolate the desired salt.
Step (a) involves providing a solution or suspension of the compound of formula (II) in a suitable solvent or solvent mixture. The solution or suspension of the compound of formula (II) can be obtained by dissolving or suspending the compound of formula (II) in a solvent or a mixture of solvents, or it can be obtained in situ, directly from the reaction in which the composed of formula (II). The suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and which can dissolve the compound of formula (II), at least to some extent. The solvent system is preferably selected so as to facilitate salt formation. The solvent (s) that can be used to dissolve or suspend the compound of formula (II) include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol and n-propanol; ketones, such as acetone, ethyl methyl ketone and methyl isobutyl ketone; asters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, dichloroethane and chloroform; hydrocarbons such as n-hexane, heptane, n-pentane, Cyclopentane and cyclohexane; or any mixture thereof. The preferred solvent is ethanol.
In step (b), the compound of formula (II) in solution or suspension is treated with a lithium cation source. The lithium cation source can be lithium hydroxide or lithium hydroxide monohydrate. In one embodiment, the compound of formula (II) is treated with lithium hydroxide monohydrate brought to a suitable solvent such as alcohol. In one embodiment, the reaction can be carried out at a temperature ranging from about -5 ° C to about the boiling point of the solvent (s). In one embodiment, the reaction can be carried out at about -5 ° C to 0 ° C. The time required to complete the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent employed. However, as long as the reaction is carried out under the conditions set forth above, a period of from about 1 hour to about 24 hours or longer is sufficient. In step (b), a solution of lithium hydroxide monohydrate in ethanol can generally be added to the solution or suspension or compound of formula (II).
Step (c) involves the isolation of the desired salt. The lithium salt of the compound of formula (II) produced in the reaction can be isolated using techniques such as decanting, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent.
In a preferred embodiment, the reaction mixture of step (b) is subjected to evaporation under reduced pressure. The solid obtained can optionally be further carried to a suitable solvent such as acetonitrile or diethyl ether and stirred for a suitable period of time. The solid can be collected by filtration. The recovered solid can be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the product is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
In another embodiment, the present invention relates to the process for the preparation of the crystalline lithium salt of the compound of formula (II) which is designated alpha form.
In a preferred embodiment, the compound of formula (II) can be carried to ethanol, for example to absolute ethanol preferably in an inert atmosphere. The reaction mass can be cooled to a temperature of -5 to 0 ° C. To the reaction mass, lithium hydroxide monohydrate can be added.
Preferably, the addition can be carried out at the temperature of -5 to 0 ° C and the reaction mass can be maintained at that temperature for about one hour.
The solid can be collected by various techniques. Isolation of the solid can be effected by methods including solvent removal, concentration of the reaction mass, or any other suitable technique. Suitable techniques that can be used for solvent removal include and are not limited to rotational distillation using a device, such as, for example, a Buchi® Rotavapor® apparatus. In a preferred embodiment, the removal of the solvent can be effected by methods including removal of the solvent under reduced pressure.
The recovered solid may optionally be dried further. The dried solid can be further stirred with a suitable solvent such as diethyl ether for a period of 1 to 2 hours. The solid can be collected by known techniques such as filtration, centrifugation or decantation.
The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at reduced pressure at suitable temperatures as long as the quality of the lithium salt of the compound of formula (II) is not degraded. He drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
In another embodiment, the present invention relates to the process for the preparation of the crystalline lithium salt of the compound of formula (II) designated alpha form, which process involves bringing the amorphous form of the lithium salt of the compound of formula (II) to diethyl ether or any other suitable solvent such as acetonitrile; Stir the reaction mass for a suitable period of time and isolate the alpha crystalline form. In this embodiment, the mixture of the amorphous form of the lithium salt of the compound of formula (II) and diethyl ether can be stirred for a period such as 1-2 hours. The solid can be collected by known techniques such as filtration. The solid obtained can be further dried for a suitable period of time at a suitable temperature optionally under reduced pressure. For example, the solid can be dried for 3-4 hours at 30-35 ° C under vacuum.
In another embodiment, the present invention relates to a pharmaceutical composition comprising excipients, carriers, diluents or mixtures thereof, and a therapeutically effective amount of the potassium salt of the compound of formula (II).
The present application also relates to the crystalline forms of N-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo- 1, 2,3,4-tetrahydrothieno [2,3-cdpyrimidin-5-yl) acetamide designated compound of formula (II): and to the process for preparing them.
In another embodiment, the crystalline forms of the compound of formula (II) of the present invention exist in an anhydrous and / or solvent-free form or as a hydrate and / or solvate form.
In another embodiment, a crystalline formula (II) compound having a water content of less than about 5% is provided.
In another embodiment, there is provided a crystalline compound of formula (II) having a water content of about 0.2-2.0% as determined by the Karl Fischer method, more preferably in the range of 0, 2 to 1.0%.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 50 m2 / gm, preferably less than 25 m2 / gm or more preferably less than 10 m2 / gm is provided.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 50 m2 / gm is provided.
In yet another embodiment, a compound of formula (II) is provided crystalline having a surface area of less than about 25 m2 / gm.
In yet another embodiment, a crystalline formula (II) compound having a surface area of less than about 10 m2 / gm is provided.
In another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 100 mlti, or preferably less than 50 mhh, or more preferably less than 20 mhh, is provided.
In another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 100 m? Ti is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 50 m? Ti is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 20 mhh is provided.
In yet another embodiment, a crystalline formula (II) compound having an average particle size (D50) of less than 10 mhh is provided.
In another embodiment, the crystalline compound of formula (II) has about 10% of the particles (Dio) having a size of less than 10 mhi, or preferably less than 5 mhi.
In yet another embodiment, the crystalline compound of formula (II) has about 10% of the particles (D10) having a size of less than 10 m? Ti.
In yet another embodiment, the crystalline formula (II) compound has about 10% of the particles (D10) that are less than 5 mhi in size.
In another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 200 mhh, or preferably less than 100 m? Ti, or more preferably less than 50 m? Ti.
In yet another embodiment, the crystalline compound of formula (II) has approximately 90% of the particles (D90) having less than 200 mhh.
In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 100 m? Ti.
In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 50 mhh.
In yet another embodiment, the crystalline compound of formula (II) has about 90% of the particles (D90) having less than 20 mpti.
In another embodiment, the present invention relates to the crystalline form of the compound of formula (II) which is designated form X.
In another embodiment, the X-shape is characterized by the powder X-ray diffraction pattern (XRPD) as shown in Figure 12.
In another embodiment, the X-shape is characterized by the IR pattern as shown in Figure 13.
In another embodiment, the X-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 11, 06, 12.84 and 13.37 ± 0.2.
In yet another embodiment, the X-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 19.93 and 24.94 ± 0.2.
In yet another embodiment, the X-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 11.06, 12.84, 13.34, 19.93 and 24.94 ± 0.2.
In another embodiment, the X-form is further characterized by the peaks of the characteristic X-ray diffraction pattern expressed in terms of 2Q as presented in Table 6.
Table 6: Two prominent theta positions and relative intensities of XRPD of form X In another embodiment, the present invention relates to another crystalline form of the compound of formula (II) which is designated form Y.
In another embodiment, the Y-shape is characterized by the powder X-ray diffraction pattern (XRPD) as shown in Figure 14.
In another embodiment, the Y-shape is characterized by the Fourier Transform Infrared Spectroscopy (FT-IR) pattern as shown in Figure 15.
In another embodiment, A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidn-5-yl) crystalline acetamide designated form Y is characterized by the Fourier transform infrared spectroscopy pattern (FT-IR) in which the ratio between the intensity of the absorption bands at wavelengths of 1500 cm 1 and 1480 cm 1 is from 1: 1, 7 to 1 : 2,4.
In another embodiment, the Y-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 20: 4.72 and 9.40 ± 0.2.
In yet another embodiment, the Y form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 20: 21, 04, 25.87 and 31, 73 ± 0.2. .
In yet another embodiment, the Y form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 4.72, 9.40, 21, 04, 25.87 and 31.73 + 0.2.
In another embodiment, the Y-shape is further characterized by the peaks of the characteristic X-ray diffraction pattern expressed in terms of 20 as presented in Table 7.
Table 7: Two prominent theta positions and relative intensities of XRPD of the Y form In another embodiment, the present invention relates to yet another crystalline form of the compound of formula (II) which is designated form Z.
In another embodiment, the Z-shape is characterized by the powder X-ray diffraction pattern (XRPD) as shown in Figure 16.
In another embodiment, the Z-form is characterized by the pattern of infrared by Fourier transform (FT-IR) as shown in figure 17.
In another embodiment, A / - [4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) crystalline acetamide designated Z-form is characterized by the Fourier transform infrared spectroscopy pattern (FT-IR) in which the ratio between the intensity of the absorption bands at wavelengths of 1500 cm 1 and 1480 cm 1 is from 1: 2.5 to 1: 2.9.
In another embodiment, the Z-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 10.63 and 19.25 ± 0.2.
In yet another embodiment, the Z-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 22.11, 22.76 and 27.27 ± 0.2. .
In another embodiment, the Z-form is further characterized by the characteristic X-ray diffraction pattern comprising one or more of the following peaks expressed in terms of 2Q: 10.63, 19.25, 22.11, 22.76 and 27.27 ± 0.2.
In another embodiment, the Z-form is further characterized by the peaks of the characteristic powder X-ray diffraction pattern expressed in 2Q terms as presented in table 8.
Table 8: Two prominent theta positions and relative intensities of XRPD of the Z form In another embodiment, the crystalline forms of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydric acid [2,3-cdpyrimidin-5-yl] acetamide, the X, Y forms and Z, can be distinguished independently or additionally by the ratio of the intensities of the absorption bands at wavelengths of 1500 cm 1 and 1480 cm 1, the highest for the X form and the lowest for the Z form as presents in table 9.
Table 9: The ratio between the absorption intensity bands at the wavelength of 1500 cm 1 and 1480 cm 1 depending on the crystalline form of the compound of formula (II) In another embodiment, the present invention provides a compound of formula (II) having a purity greater than about 99.0%.
In another embodiment, the present invention provides a compound of formula (II) having a purity greater than about 99.5%.
In another embodiment, the present invention provides a compound of formula (II) having less than about 0.1% (by HPLC) of the compound of formula (III): In another embodiment, the present invention provides a crystalline compound of formula (II) having a purity greater than about 99.8%.
In another embodiment, the present invention provides a compound of formula (III) _ or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to the process for the preparation of the crystalline form of the compound of formula (II) which is designated form X, which process involves the following steps: I. bringing the compound of formula (II) to an alcohol solvent and stirring the mixture; Y II. Isolate the solid.
In step I, the compound of formula (II) is brought to an alcohol, preferably methanol or isopropanol. In a preferred embodiment, the solvent is methanol. The mixture can be stirred at the appropriate temperature.
In a preferred embodiment, the mixture can be stirred at 25-30 ° C for a suitable period of time. The appropriate period can be in the range of from 1 hour to 24 hours.
In stage II, the desired shape is isolated. Isolation of the solid can be effected by techniques known in the art, including but not limited to, decanting, filtration by gravity or suction, centrifugation or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the compound of formula (II) is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
The compound of formula (II) of step I can be obtained by the coupling of (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydric acid [2,3-c]). /] pyrimidin-5-yl) acetic acid with 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine using a suitable coupling agent, in the presence of a base adequate in a suitable solvent. The coupling agent used can be hydroxybenzotriazole (HOBt) or (1- (3-dimethylaminopropyl) -3-etlcarbodlimide) or mixtures thereof. The base used for the coupling can be 4-dimethylamino-pyridine. The solvent used can be 1,2-dichloroethane.
In another aspect, the present invention relates to the process for the preparation of the crystalline form of the compound of formula (II) which is designated form Y, which process involves the following steps: (I) bringing the compound of formula (II) to a halogenated solvent; Y (II) isolate the solid.
In step I, the halogenated solvent can be dichloromethane.
In stage II, the desired shape is isolated. The isolation of the solid can be effected by techniques known in the art, including but not limited to, decantation, filtration by gravity or suction, centrifugation or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying can be carried out at atmospheric pressure or at a reduced pressure at suitable temperatures as long as the quality of the compound of formula (II) is not degraded. The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
The compound of formula (II) of step I can be obtained by coupling acid (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c / jpyrimidin-5] -yl) acetic acid with 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine using a suitable coupling agent, in the presence of a suitable base in a suitable solvent. The coupling agent used can be hydroxybenzotriazole (HOBt) or (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) or mixtures thereof. The base used for the coupling can be A / -methylmorpholine. The solvent used can be dichloromethane.
In another aspect, the present invention relates to the process for the preparation of the crystalline form of the compound of formula (II) which Z is designated form, procedure that involves the following stages: (I) bringing the compound of formula (II) to a polar solvent and stirring the mixture; (II) add water to the mixture and (III) isolate the solid.
In step I, the compound of formula (II) is brought to a polar solvent. In a preferred embodiment, the solvent is DMSO. The mixture can be stirred at the appropriate temperature. In a preferred embodiment, the mixture can be stirred at 50-60 ° C for a suitable period of time. The appropriate period may be until a clear solution of the mixture is observed. Vegetable charcoal can also be added to the mixture and the mixture can be filtered before the addition of water.
In stage III, the desired shape is isolated. Isolation of the solid can be effected by techniques known in the art, including but not limited to, decanting, filtration by gravity or suction, centrifugation or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. The recovered solid may optionally be dried further. The drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, instant rotary dryer, instant dryer, or the like. The drying may be carried out at atmospheric pressure or at reduced pressure at suitable temperatures as long as the quality of the product is not degraded. composed of formula (II). The drying can be carried out for any desired time until the required purity is achieved. For example, it may vary between about 1 and about 10 hours or longer.
The crystalline form Z of the compound of formula (II) can also be obtained from the Y form of the compound of formula (II).
In another embodiment, the present invention relates to a pharmaceutical composition comprising excipients, carriers, diluents or mixtures thereof, and a therapeutically effective amount of crystalline formula (II) compound designated Y form.
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with the function of TRPA1 in a subject in need thereof by administering to the subject an effective amount of the potassium salt of the compound of formula (II).
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the Initial value of about 0.80% to about 16.0% in 48 h at 25 ° C / RH of the 90%, or a pharmaceutical composition comprising said potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 6.6% in 48 h at 25 ° C / RH of the 80%, or a pharmaceutical composition comprising said potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the potassium salt of the compound of formula (II) having the gradual increase in moisture content from the initial value of about 0.80% to about 3.5% in 48 h at 25 ° C / RH of the 60%, or a pharmaceutical composition comprising said potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a solid state form of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising the solid state form of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering form I or form II or amorphous form of the potassium salt of the compound of formula (II), or a pharmaceutical composition comprising form I or form II or the amorphous form of the potassium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a pharmaceutical composition comprising excipients, carriers, diluents or mixtures thereof, and a therapeutically effective amount of the sodium salt of the compound of formula (II).
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with the function of TRPA1 in a subject in need thereof by administering to the subject an effective amount of the sodium salt of the compound of formula (II).
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a solid state form of the sodium salt of the compound of formula (II), or a pharmaceutical composition comprising the solid state form of the sodium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; what comprises administering an amorphous form of the sodium salt of the compound of formula (II), or a pharmaceutical composition comprising the amorphous form of the sodium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a crystalline form A of the sodium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline form A of the sodium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a pharmaceutical composition comprising excipients, carriers, diluents or mixtures thereof, and a therapeutically effective amount of the lithium salt of the compound of formula (II).
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with the function of TRPA1 in a subject in need thereof by administering to the subject an effective amount of the lithium salt of the compound of formula (II).
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a solid state form of the lithium salt of the compound of formula (II), or a pharmaceutical composition comprising the solid state form of the lithium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a crystalline form of the lithium salt of the compound of formula (II), or a pharmaceutical composition comprising the crystalline form of the lithium salt of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with TRPA1 that are selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, pain due to rheumatoid arthritis, pain due to osteoarthritis, lumbago, visceral pain, pain due to cancer, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, pain after stroke, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, esophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, vomiting, gastroduodenal ulcer and pruritus by administration of salt of potassium, lithium or sodium of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide.
In one embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering a salt of the compound of formula (II), or a pharmaceutical composition comprising the salt of the compound of formula (II) together with pharmaceutically acceptable excipients, wherein the salt of the compound of formula (II) is a salt of potassium, a sodium salt or a lithium salt.
In one embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering solid state salt forms of the compound of formula (II), or a pharmaceutical composition comprising the solid state salt forms of the compound of formula (II) together with pharmaceutically acceptable excipients, wherein the salt of the compound of formula (II) is a potassium salt, a sodium salt or a lithium salt.
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with the function of TRPA1 in a subject in need thereof by administering to the subject an effective amount of crystalline formula (II) compound designated Y form In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the X-form of the compound of the formula (II), or a pharmaceutical composition comprising the X-form of the compound of the formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the Y form of the compound of formula (II), or a pharmaceutical composition comprising the Y form of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, a method is provided for treating diseases, conditions and / or disorders modulated by TRPA1; which comprises administering the Z form of the compound of formula (II), or a pharmaceutical composition comprising the Z form of the compound of formula (II) together with pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a method of treating diseases or conditions or disorders associated with TRPA1 that are selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, pain due to rheumatoid arthritis, pain due to osteoarthritis, lumbago, visceral pain, pain due to cancer, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, pain after stroke, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, esophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome, inflammatory disease of the intestine, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, vomiting, gastroduodenal ulcer and pruritus by administration of form X, form Y or form Z of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide.
Preparation methods The compounds described herein, including compounds of general formula (I), or compound of formula (II) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in the scheme a continuation as well as by other methods. In addition, in the following schemes, in which acids, bases, reagents, coupling agents, specific solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. can be used. and are included within the scope of the present invention. Modifications of the reaction conditions are envisaged, for example, temperature, reaction duration or combinations thereof, such as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for the purification of organic compounds known to those skilled in the art, for example, crystallization or column chromatography on silica gel or alumina using different solvents in suitable ratios. All possible geometric isomers and stereoisomers are contemplated within the scope of this invention.
In one embodiment, there is provided a process for the preparation of the compound of formula (II) and its pharmaceutically acceptable salt, which process comprises the following steps as shown in scheme 1 below.
Scheme 1: ø Stage b O «C ¥ B e O COOREBack d H, C- NS «c ~ tA NaSH ¾C'N, i). N ^ V C Ciicciiaacciióórn 0 > Stage a O ^ t CI solvent I baS € dsolvent °? S 'solvent CH OH CH, Stage c CH, (1) (2) (4) NaH / solvent The procedure comprises the following steps: a) treating dimethylbarbituric acid with a suitable chlorinating agent to provide 6-chloro-1,3-dimethyluracil of formula (1); b) treating 6-chloro-1,3-dimethyluracil of formula (1) with sodium hydrous hydrate to give the 6-mercapto-1,3-dimethyluracil of formula (2); c) treating the 6-mercapto-1,3-dimethyluracil of formula (2) with the compound of formula (3) to give the ester compound of formula (4); d) Cementing the ketoester of formula (4) to obtain the thieno-pyrimidinyl ester of formula (5); e) reacting the thieno-pyrimidinyl ester of formula (5) with the thiazolamine of formula (7) to give the compound of formula (II). Alternatively, hydrolyze the compound of formula (5) to give the thieno-pyrimidinyl-acetic acid of formula (6), followed by reacting the compound of formula (6) with the thiazolamine of formula (7).
Step (a) involves reacting the dimethylbarbituric acid with a chlorinating agent. The chlorinating agent comprises phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride. The reaction can be carried out in a suitable solvent such as water at a suitable temperature, which involves heating the reaction mixture to the reflux temperature.
Step (b) involves treating the compound of formula (1) with sodium hydrate hydrate to give the compound of formula (2). The reaction can be carried out in a suitable solvent. The suitable solvent comprises C1-C6 alcohols, chlorination solvent, water and / or mixtures thereof. Preferably, the suitable solvent (s) that can be used in step (b) are ethanol, chloroform and / or a combination thereof. The reaction is preferably carried out in a temperature range of 0-5 ° C. Preferably, the reaction can be carried out using ethanol as solvent followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the obtained residue was dissolved in water and extracted with dichloromethane. The aqueous phase was separated and acidified with HCl 1 N. The precipitated solid was filtered, washed with water and dried to obtain the compound of formula (2).
Step (c) involves reacting the compound of formula (2) with the compound of formula (3), (wherein R is (Ci-C4) alkyl, eg, methyl or ethyl) to give the ester compound of formula (4), (wherein R is (C1-C4) alkyl). The reaction can be carried out optionally in the presence of a suitable base and suitable solvent (s). Bases that are useful in the reaction include, but are not limited to, organic bases, such as tertiary amines, for example, triethylamine, N, A / -diisopropylethylamine, N, / V-diethylethanamine, / V- (1 - methylet) -2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo [2.2.2] -octane, / V-methylmorpholine, pyridine and the like; or any mixture thereof.
The reaction can be carried out in a suitable solvent or solvent mixture. In one of the embodiments, the reaction is carried out in a chlorinating solvent. The chlorinating solvent includes dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride. Another suitable solvent can also be used.
The reaction can be carried out at a suitable temperature, preferably at room temperature (~ 25 to 30 ° C).
Step (d) involves cyclizing the ester compound of formula (4) to obtain the thieno [2,3-jpyrimidinyl ester of formula (5). The cyclization stage it can be carried out using a suitable dehydrating agent such as polyphosphoric acid, phosphorus pentoxide, zinc chloride, sulfuric acid, boron trifluoride or Pd2 (dba) 3 and Xantphos. The reaction can be carried out in a suitable solvent or can be carried out in the absence of a solvent. Advantageously, the reaction can be carried out at an elevated temperature such as 60-70 ° C or it can be carried out at a reflux temperature of the solvent employed in the reaction.
Step (e) involves reacting the compound of formula (5) with the amine of formula (7) in the presence of a suitable base and a suitable solvent to give the compound of formula (II). The reaction can be carried out in the presence of a suitable base. The suitable base includes inorganic and organic bases such as, for example, sodium hydride. The suitable solvent may include, but is not limited to, hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane. The reaction can be carried out at an elevated temperature such as the reflux temperature of the solvent or mixture of solvents used. Preferably, the base used in step (e) is sodium hydride and a solvent such as toluene.
In an alternative route, step (e1) involves the ester hydrolysis of the compound of formula (5) to obtain the compound of formula (6). In this step, the ester hydrolysis can be carried out using acid (for example, H2SO4 or HCl) or base (for example, sodium hydroxide, potassium hydroxide or lithium hydroxide) under suitable conditions (e.g., at reflux temperature) in the presence of a suitable solvent such as alcohol, water or 1,4-dioxane and / or a combination thereof. Preferably, the ester hydrolysis can be carried out using H 2 SO 4 N or 6 N in 1,4-dioxane at the reflux temperature.
In the next step (e2), the compound of formula (6) can be coupled with the compound of formula (7) in the presence of coupling reagent. Suitable coupling reagents include, but are not limited to, / V-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCI), 1,1'-carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis [[4- (2,2-dimethyl-1,3-dioxolyl)] - methyljcarbodiimide, N, N'-bis (2-) chloride oxo-3-oxazolidinyl) -phosphine (BOP-CI). The coupling can be carried out in the presence of a suitable base and a suitable solvent. Alternatively, the acid group of the compound of formula (6) can be converted to its acid chloride by treating it with a chlorinating agent such as oxalyl chloride or thionyl chloride in a suitable solvent, followed by treatment of the acid chloride derivative with the compound of formula (7) in the presence of a base such as triethylamine, pyridine or diisopropylamine in a suitable solvent to give the compound of formula (II).
In another embodiment, a method for the preparation of A / - is provided. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3- dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (! pyrimidin-5-yl) acetamide or the pharmaceutically acceptable salt thereof, the process comprising the step of (a) treating dimethylbarbituric acid with a suitable chlorinating agent to provide 6-chloro-1,3-dimethyluracil of formula (1); Y (b) treating 6-chloro-1,3-dimethyluracil of formula (1) with sodium hydrosulphur hydrate to give 6-mercapto-1,3-dimethyluracil of formula (2).
O Stage b O NaSII ¾c diSOlV6rite O ^ N 'SH c% (c) treating the 6-mercapto-1,3-dimethyluracil of formula (2) with the compound of formula (3) wherein R is (C1-C4) alkyl, to give the ester compound of formula (4); Y (d) Cementing the ketoester of formula (4) to obtain the thieno-pyrimidinyl ester of formula (5) Step (a) involves reacting the dimethylbarbituric acid with a chlorinating agent. The chlorinating agent comprises phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride. The reaction can be carried out in a suitable solvent such as water at a suitable temperature, which involves heating the reaction mixture to the reflux temperature.
Step (b) involves treating the compound of formula (1) with sodium hydrate hydrate to give the compound of formula (2). The reaction can be carried out in a suitable solvent. The suitable solvent comprises C1-C6 alcohols, chlorination solvent, water and / or mixtures thereof. Preferably the suitable solvent (s) can be used in step (b) are ethanol, chloroform and / or a combination thereof. The reaction is preferably carried out in a temperature range of 0-5 ° C. Preferably, the reaction can be carried out using ethanol as solvent followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the obtained residue was dissolved in water and extracted with dichloromethane. The aqueous phase was separated and acidified with 1N HCi. The precipitated solid was filtered, washed with water and dried to obtain the compound of formula (2).
Step (c) involves reacting the compound of formula (2) with the compound of formula (3), (wherein R is (C 1 -C 4) alkyl, eg, methyl or ethyl) to give the ester compound of formula (4), (wherein R is (C1-C4) alkyl). The reaction can be carried out optionally in the presence of a suitable base and suitable solvent (s). Bases that are useful in the reaction include, but are not limited to, organic bases, such as tertiary amines, for example, triethylamine, N, / V-diisopropylethylamine, N, A / -diethylethanamine, A / - (1-methyl-ethyl) -2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo [2.2.2] -octane, / V-methylmorpholine, pyridine and the like; or any mixture thereof.
The reaction can be carried out in a suitable solvent or solvent mixture. In one of the embodiments, the reaction is carried out in a chlorinating solvent. The chlorinating solvent includes dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride. Another suitable solvent can also be used.
The reaction can be carried out at a suitable temperature, preferably at room temperature (~ 25 to 30 ° C).
In another embodiment of the present invention, a Process for the preparation of the compound of formula (II) and its pharmaceutically acceptable salt, comprising the steps of: f) reacting the thioglycol ester of formula (4) with the amine of formula (7) to provide the thioglycol amide of formula (8); Y g) the thioglycol amide of formula (8) The stages (f) and (g) mentioned above are represented in scheme 2 Scheme 2: In step (f), the thioglycol ester of formula (4) (wherein R is (C 1 -C 4) alkyl, eg, methyl or ethyl) is reacted with the amine of formula (7) in the presence of a Suitable base and a suitable solvent to give the thioglycol amide of formula (8). The appropriate base can include organic or inorganic base. In one of the embodiments, the base used is sodium hydride. The suitable solvent may include, but is not limited to, hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane. In the next step (g), the compound of formula (8) is cyclized to obtain the compound of formula (II). Cyclization can be carried out using dehydration agent. The agents of Suitable dehydration are such as polyphosphoric acid, phosphorus pentoxide, zinc chloride, sulfuric acid and boron trifluoride. The reaction can be carried out in a suitable solvent. The suitable solvent may include, but is not limited to, hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane or may be carried out in the absence of a solvent. Advantageously, the reaction can be carried out at an elevated temperature such as 60-70 ° C or it can be carried out at a reflux temperature of the solvent employed in the reaction.
In another embodiment, the present invention relates to the process for the preparation of the compound of formula (II) and its pharmaceutically acceptable salt, which comprises the following steps: h) reacting the thieno [2,3-c / j-pyrimidinyl-acetic acid of formula (6) with 1H-1,2,3-benzotriazole (9) to obtain the N-acylbenzotriazole derivative of formula (10); Y i) reacting the / V-acylbenzotriazole derivative of formula (10) with the amine compound of formula (7) to provide the compound of formula (II).
The steps (h) and (i) mentioned above are represented in scheme 3.
Scheme 3: HjC ¾- < Q "r O ^ N ¾¾ L¾¾ ag "'m < P« ¾ i; "Wr nte * Se coupting, CHj 6 * », i« ¾Wte Stage i (6) m (ÍI) In this approach, in step (h) the thieno [2,3-] pyrimidinyl-acetic acid of formula (6) is converted to the / V-acylbenzotriazole derivative of formula (10) by the reaction of the compound of formula ( 6) with 1H-1, 2,3-benzotriazole (9) in the presence of SOCI2 and in a suitable solvent. In one embodiment, the suitable solvent is a chlorinated solvent, for example, dichloromethane. In the next step (i), the reaction of the / V-acylbenzotriazole derivative of formula (10) with the amine compound of formula (7) can be carried out in the presence of a suitable base to provide the compound of formula (II) ).
In another embodiment, another method is provided for the preparation of the compound of formula (II) and its pharmaceutically acceptable salt, which comprises the following steps: j) hydrolyzing the compound of formula (4) to obtain the corresponding acid compound of formula (11); k) reacting the compound of formula of (11) with the compound of formula (7) to obtain the compound of formula (8); Y l) cyclizing the compound of formula (8) to provide the compound of formula (II).
The steps (j), (k) and (I) mentioned above are represented in scheme 4.
Scheme 4: ¾ measure In this approach, hydrolysis of the thioglycol ester of formula (4) (wherein R is (Ci-C4) alkyl, for example, methyl or ethyl) in the presence of a base or a suitable acid provides the thioglycolic acid of formula ( eleven). Coupling of the compound of formula (11) with the compound of formula (7) in the presence of a suitable coupling agent and a suitable solvent provides the thioglycol amide compound of formula (8). Cyclization of the thioglycol amide compound of formula (8) in the presence of a dehydration agent as described in scheme 1 provides the desired compound of formula (II).
In a further embodiment, the process is provided for the preparation of the compound of formula (5) comprising the following steps: m) reacting the compound of formula (12) with sulfide of sodium hydrate and ethyl cyanoacetate to obtain the compound of formula (13); n) bromating the compound of formula (13) to obtain the compound of formula (14); Y o) converting the compound of formula (14) to the compound of formula (5).
The stages (m), (n) and (o) mentioned above are represented In the present document, ethyl 4-bromoacetoacetate and ethyl cyanoacetate can be coupled in the presence of hydrous sodium sulfide to give the amino compound of formula (13). The product obtained can be treated with t-butyl nitrite followed by copper bromide to provide the bromo compound of formula (14). The overhead of (14) using / V, / V-dimethylurea in the presence of a palladium reagent such as tris (dibenzylidene ketone) dipalladium (0) (Pd2 (dba) 3) gives the desired ester compound of formula (5 ') .
In a further embodiment, there is provided a process for the preparation of the compound of formula (7) which comprises treating a solution of 1- [2,4-difluoro-3- (trifluoromethyl) phenyl] ethanone (16) in glacial acetic acid with liquid bromine to obtain the crude bromine derivative. The crude bromine derivative, without further purification can be treated with thiourea to provide the 2-amino-4-aryl-thiazole compound (7). Alternatively, 1- [2,4-difluoro-3- (trifluoromethyl) phenyl] ethanone (16), iodine and thiourea in ethanol can be refluxed to provide the compound of 4- [2,4-difluoro-3- ( trifluoromethyl) phenyl] -1,3-thiazol-2-amine (7).
Scheme 6: You Pharmaceutical compositions The compounds of the invention are usually administered in the form of a pharmaceutical composition. Such compositions can be prepared using methods well known in the pharmaceutical arts and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Normally, pharmaceutically acceptable excipients are approved by the regulatory authorities or are generally considered safe for use with humans or animals. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, stearate. magnesium, talc, gelatin, agar, pectin, gum arabic, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of fatty acids, esters of fatty acids and polyoxyethylene.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preservatives, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. In addition, the pharmaceutical composition of the present invention can be formulated so as to provide the desired release profile.
The administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of the pharmaceutical compositions. The route of administration can be any route that efficiently transports the active compound from the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in the form of a powder or granule), troches and lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eyedrops or eardrops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to aid in the penetration of the drug.
The pharmaceutical compositions of the present patent application they can be prepared by conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams &Wilkins).
Suitable doses of the compounds for use in the treatment of the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are usually identified through a dose determination study in humans based on preliminary evidence derived from animal studies. The doses should be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. The mode of administration, dosage forms and suitable pharmaceutical excipients can also be used and well adjusted by those skilled in the art. All changes and modifications are provided within the scope of the present patent application.
Definitions The term "crystalline" as used herein, means that it has a regularly repeating arrangement of molecules or planes of an external face.
The term "amorphous" as used herein, means essentially without a regularly repeating arrangement of molecules or planes of an external face.
Unless stated otherwise, the percentages established throughout this specification are percentages in weight / weight (P / P) · The term "mixture" as used herein, means a combination of at least two substances, in which one substance can be completely soluble, partially soluble or essentially insoluble in the other substance.
The term "treat" or "treatment" of a state, disorder or condition includes; (a) preventing or delaying the onset of clinical symptoms of the condition, disorder or condition that develop in a subject who may be afflicted with or predisposed to the condition, disorder or condition but who does not experience or still have clinical or subclinical symptoms of the condition, disorder or condition; (b) inhibiting the condition, disorder or condition, i.e., stopping or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) alleviating the disease, i.e., causing regression of the condition, disorder or condition or at least one of its clinical or subclinical symptoms.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (eg, pets including cats and dogs) and non-domestic animals (such as wildlife).
All dust X-ray diffraction patterns were obtained using the Panalytical X'PERT-PRO diffractometer model and were measured with Cu Kct1 radiation at the wavelength of 1, 54060 A °. The powder X-ray diffraction profiles obtained using the X'Pert High Score Plus software were integrated.
It is intended that it be understood that peak heights in a powder X-ray diffraction pattern may vary and will depend on variables such as temperature, crystal size, crystalline habit, sample preparation or sample height. in the analysis well of the Scintagx2 diffraction pattern system.
All FTIR spectra were recorded using KBr in the Perkin-Elmer instrument (model: Spectrum One). The data was processed using the Spectrum One software.
As used herein, the term "average particle size" (or synonymously, "average particle size") refers to the particle distribution, in which approximately 50 volume percent of all the measured particles have a size smaller than the defined average particle size value, and approximately 50 volume percent of all measured medium particles have a particle size greater than the defined average particle size value. This can be identified by the term "D50" or "d (0.5)".
The term "D10" refers to the distribution of particles, in which about 10 volume percent of all the measured particles have a size smaller than the defined average particle size value. This can be identified by the term "d (0,1)" as well. Similarly, as used herein, the term "D90" refers to the particle distribution, wherein approximately 90 volume percent of all the measured particles have a size smaller than the size value of the particles. average particle defined. This can be identified by the term "d (0.9)" as well.
The average particle size can be measured using various techniques such as laser diffraction, photon correlation spectroscopy and the Coulter principle. Normally, instruments such as ZETASIZER® 3000 HS (Malvern® Instruments Ltd., Malvern, United Kingdom), the NICOMP 388 ™ ZLS system (PSS -Nicomp Partiole Sizing Systems, Santa Barbara, CA, USA) or the Coulter counter to determine the average particle size. Preferably, the Mastersizer 2000 instrument is used (Malvern® Instruments Ltd., Malvern, United Kingdom) to determine the particle size of the particles.
Experimental part Unless stated otherwise, the final treatment includes the distribution of the reaction mixture between the organic and aqueous phases indicated in parentheses, the separation of the phases and the drying of the organic phase over sodium sulfate, filtration and evaporation. of the solvent. The purification, unless otherwise mentioned, includes purification by chromatography techniques on silica gel, generally using a mixture of ethyl acetate / petroleum ether of a suitable polarity as the mobile phase. The use of a different eluent system is indicated in parentheses. The following abbreviations are used in the text: DMSO-d6: hexadeuterodimethylsulfoxide; AcOEt: ethyl acetate; equiv. or eq .: equivalents; h: hour (s); I: liters; CDCl 3: deuterated chloroform; CHCl3: chloroform; EtOAc or EA: ethyl acetate; DCM: dichloromethane; DMSO: dimethylsulfoxide; DMF: / V, A / -dimethylformamide; DSC: differential scanning calorimetry; EDCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide); HOBt: hydroxybenzotriazole; Cs2CO3: cesium carbonate; K2C03: potassium carbonate; MeOH: methanol; EtOH: ethanol; NaHCO 3: sodium bicarbonate; Na2C03: sodium carbonate; NaOtBu: sodium tert-butoxide; KOtBu: potassium tert-butoxide; PCI5: phosphorus pentachloride; POCI3: phosphorus oxychloride; THF: tetrahydrofuran; TEA: triethylamine; TBAF: tetra-n-butylammonium fluoride; J: coupling constant in units of Hz; T.A. or t.a .: room temperature (22-26 ° C); c.s .: sufficient quantity; ac .: aqueous; equiv. or eq .: equivalents; conc .: concentrated; min: minutes; i.e .: that is; h or hrs: hours.
The parameters mentioned in the description that characterize the polymorphic nature, moisture content, particle size, stability studies using measurement techniques and methods described below: Hygroscopicity study: The hygroscopicity study was carried out under the following conditions: the material was exposed to a relative humidity condition (for example, 60%, 80%, 90%) at 25 ° C. The material was thinly spread in a dried and pre-weighed Petri dish. The plate was exposed to conditions of relative humidity at 25 ° C. The Petri dish was removed at regular intervals and weighed. Samples were tested to determine the description and moisture content by the Karl Fischer method.
Studies of particle size distribution: The particle size distribution was measured using the Mastersizer 2000 instrument (Malvern® nstruments Ltd., Malvern, UK) with the following settings and measurement equipment: Instrument: Malvern Mastersizer 2000 Sample handling unit: Hydro 2000S (A) IR of the dispersant: 1, 375 Dispersant: sodium salt of dioctyl sulfosuccinate 0.1% w / v in n-hexane Sample quantity: 100 mg Measuring time: 5.0 s X-ray powder diffraction studies: All dust X-ray diffraction patterns were obtained using: the Panalytical X'PERT-PRO diffractometer model and were measured with Ka1 radiation of Cu at the wavelength of 1.54060 A °. The powder X-ray diffraction profiles obtained using the X'Pert High Score Plus software were integrated.
Stability test methods: The salts of the compound of formula II were stored under conditions as shown in table 11 and the total amount of degradation products (related substances) and maximum individual impurity formed during storage was estimated according to the following protocol: HPLC conditions: Apparatus: a high resolution liquid chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector connected to a data logger and Integrator software or equivalent.
Column: Phenomenex Prodigy, 250 mm X 4.6 mm, 5.0 m or equivalent Mobile phase: A: buffer B: acetonitrile (for the sodium salt), acetonitrile: methanol (6: 4) for the potassium salt Buffer: 0.1% formic acid in water Diluent: acetonitrile Flow rate: 1.0 ml / minute Detection wavelength: UV 265 nm Column temperature: 40 ° C Injection volume: 20 ml Execution time: 60 min Test dissolution: 10 mg of the compound were weighed and transferred into a 20 ml volumetric flask. Dimethyl sulfoxide was added and sonicated to dissolve it. The diluent was added to bring the solution up to the mark of the flask.
Process: Equal volumes of blank (diluent) and test solution were injected separately into the liquid chromatograph. The responses were recorded by eliminating the peaks due to the blank and the chromatographic purity by area was calculated by the normalization method.
The following examples are presented to provide what is believed to be the most useful and easily understood description of the methods and conceptual aspects of this invention. The examples given below are merely illustrative of the invention and are not intended to limit the scope thereof to the embodiments given to know. It is intended that the variations and obvious changes for a person skilled in the art be within the scope and nature of the invention.
Intermediate product 1 Preparation of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine Method A: Stage 1: Synthesis of 1-bromo-2,4-difluro-3- (trifluoromethyl) benzene A mixture of 2,6-difluorobenzotrifluoride (100 g, 0.55 mol) and iron powder (20 g, 0.36 mol) was heated to 50-55 ° C and the reaction mixture was stirred for 5 min. Bromine (124 g, 0.77 mol) was slowly added to the reaction mixture at 50-55 ° C and further stirred for 2.0 h at 65-70 ° C. After completion of the reaction, it was cooled to room temperature and diluted with dichloromethane (800 ml). The reaction mixture was filtered through a Hyflo pad and washed with dichloromethane (200 ml). The filtrate obtained was washed with 10% sodium thiosulfate solution (200 ml) followed by water (200 ml) and saturated brine solution (100 ml). The organic extract was separated, dried (Na2SO4) and concentrated to obtain 130 g of the product. 1 H-NMR (300 MHz, CDCl 3): d 7.40 (t, 1 H), 8.16 (q, 1H).
Stage 2: - Synthesis of 1- (2,4-d-fluoro-3- (trifluoromethyl) phenyl) ethanone To a solution of 1-bromo-2,4-difluoro-3- (trifluoromethyl) benzene (10 g, 0.038 mol) in dry tetrahydrofuran (325 ml) was added magnesium metal (7.8 g, 0.33 mol) and the mixture was heated to 60-65 ° C to start the reaction. Again, 1-bromo-2,4-difluoro-3- (trifluoromethyl) benzene (55 g, 0.21 mol) was added carefully and the mixture was further stirred at 60-65 ° C for 1.0 h. The reaction mixture was cooled to 25-30 ° C and cadmium chloride (6.5 g, 0.035 mol) was added and stirred for 30 min. Acetic anhydride (32.3 g, 0.32 mol) was slowly added and the mixture was stirred for 1 h at room temperature. The mixture was quenched with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic extract was washed with water, brine and dried (Na2SO4). The solvent was evaporated under reduced pressure to obtain 65 g of the product as an oily mass. The product was purified by high vacuum distillation yielding 41 g of the title product. 1 H-NMR (300 MHz, CDCl 3): d 8.14 (q, 1H), 7.11 (t, 1 H), 2.66 (d, 3H).
Step 3: Synthesis of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine To a solution of 1- [2,4-difluoro-3- (trifluoromethyl) phenyl] ethanone (20 g, 0.089 mol) in acetic acid (80 ml) was slowly added bromine (18 g, 0.11 mol) in acetic acid (80 ml) at 25-30 ° C. The reaction mixture was heated to 55-60 ° C and further stirred for 30 min. Thiourea (15 g, 0.19 mol) was added in one batch and the temperature was raised to 85-90 ° C. The reaction mass was stirred at 85-90 ° C until the reaction was complete. The acetic acid was evaporated under reduced pressure and diluted with water (200 ml) and the pH of the solution adjusted to 9-10 by the addition of 30% sodium hydroxide solution. The reaction mass was stirred for 1.0 h at 25-30 ° C and the precipitated product was collected by filtration. The product was washed with water and the wet cake was dissolved in ethyl acetate (200 ml) and dried over anhydrous sodium sulfate (Na 2 SO 4). Activated charcoal (2 g) was added to the solution and stirred for 30 min. The reaction mixture was filtered through a Hyflo bed to remove charcoal. The filtrate was evaporated under reduced pressure. Hexane (40 ml) was added to the residue. The reaction mass was stirred for 1.0 h and the product was collected by filtration. The solid was washed with hexane (40 ml) and dried at 45-50 ° C to obtain 19.5 g of the title product. 1 H NMR (300 MHz, CDCl 3): d 8.28 (q 1 H), 7.41 (t 1 H), 7.19 (s, 2 H), 7.05 (d, 1 H).
Method B; Stage 1: Synthesis of 2,4-difluoro-3- (trifluoromethyl) benzoic acid To a stirring solution of 2,6-difluorobenzotrifluoride (250 g, 1.37 mol) in a mixture of THF (1.5 I) and diethyl ether (1.5 I) was added n-butyllithium dropwise. (1.0 L, 1.60 mol) at -65 ° C to -70 ° C and the resulting mixture was stirred for 1 h. Dry carbon dioxide gas was purged in the reaction mass and the temperature was allowed to warm from -65 ° C to 30 ° C for 5 h. The reaction mixture was quenched in 3N hydrochloric acid and the pH was adjusted to approximately 2. The reaction mixture was extracted with ethyl acetate and the phases were separated. The organic phase was washed with water followed by brine. The organic phase was distilled off and the viscous residue was diluted with hexane (500 ml). The precipitated solid was collected by filtration and dried to obtain 225 g of the title product (72%).
Stage 2: Synthesis of 2,4-difluoro-A / -methoxy - / \ / - methyl-3- (trifluoromethyl) benzamide To a stirring solution of 2,4-difluoro-3- (trifluoromethyl) benzoic acid (150 g, 0.66 mol) in dichloromethane (1.5 I) was added DMF (15 mL) followed by dropwise addition. Oxalyl chloride drop (76.5 ml, 0.88 mol) at room temperature and the resulting mixture was stirred for 3 to 7 h at the same temperature. After completion of the reaction, the dichloromethane was removed by vacuum distillation. The obtained acid chloride was dissolved in dichloromethane (750 ml) and the solution was used for the next step.
To a stirring solution of h /, O-dimethyl-hydroxylamine hydrochloride (70.5 g, 0.72 mol) in dichloromethane (750 ml) was added triethylamine (225 ml) and the resulting mixture was stirred for 1 h to result in a thick white suspension. The above acid chloride was added in dichloromethane and the reaction mixture was stirred for 2 h. The mixture was quenched with water (1.5 I) and extracted with dichloromethane (2 x 350 mL). The combined extract was washed with water followed by brine. The organic phase was dried over Na2SO4 and the solvent was removed by vacuum distillation to obtain 175 g (97%) of the title compound.
Stage 3: Synthesis of 1- [2,4-difluoro-3- (trifluoromethyl) phenyl] ethanone A solution of 2,4-difluoro-A / -methoxy-A / -methyl-3- (trifluoromethyl) benzamide (165 g, 0.61 mol) in dry THF (825 ml) was added to a 1.4 M solution of methylmagnesium bromide in dry THF (561 ml, 0.78 mol) with stirring and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 10% aqueous ammonium chloride solution (1.65 L) and extracted with ethyl acetate (2 x 825 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed by distillation in vacuo to give 105 g (76%) of the title compound.
Step 4: Synthesis of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine To a stirring solution of 1 - [2,4-difluoro-3- (trifluoromethyl) phenyl] ethanone (664 g, 2.96 mol) in acetic acid (3.4 I) was added dropwise a solution of bromine (193 ml, 3.76 mol) in acetic acid (2.6 I) at room temperature and the resulting mixture was stirred at 55-60 ° C for 30 min. Thiourea (477 g, 6.22 mol) was added and the mixture was stirred at 85-90 ° C for 3 h. After completion of the reaction, the acetic acid was evaporated in vacuo. The reaction mixture was cooled to room temperature, diluted with water (6.6 L). The pH of the mixture was adjusted to 9-10 using 30% sodium hydroxide solution and stirred for 3 h. The mixture was filtered and the product was washed with water. The wet material was dissolved in ethyl acetate (4.0 L) and 60 g of charcoal was added and stirred for 30 min. The mixture was filtered through Celite and the filtrate was dried over Na2SO4. The ethyl acetate was evaporated and the residue obtained was stirred in hexane (1.3 L) for 1 h. the separated solid product was collected by filtration to obtain 640 g (76%) of the title product.
Purification of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine Method I: Step-1: Malonate salt preparation of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine: To a stirring solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (5.0 g, 0.017 mol) in ethyl acetate (20 ml) was added malonic acid (2.25 g, 0.021 mol) and the reaction mixture was stirred for 1 h. Hexane (40 ml) was added to the mixture and the precipitated salt was collected by filtration and dried to yield 6.3 g (91%) of the product. 1 H-NMR (300 MHz, CDCl 3): d 12.6 (at 2 H), 8.2 (q, 1 H), 7.4 (t, 1 H), 7.2 (S, 2 H), 7.0 ( d,, 1 H), 3.2 (s, 2H).
Step 2: Preparation of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine To an agitated solution of malonate salt of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine in ethyl acetate or dichloromethane was added an aqueous solution of sodium hydroxide followed by final treatment to obtain 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine.
Method II: Step 1: Preparation of PTSA salt of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine To a stirring solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amino (240 g, 0.85 mol) in ethyl acetate (1.4 L) p-toluenesulfonic acid (162 g, 0.85 mol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was heated to 75-80 ° C and methanol (960 ml) was added dropwise thereto. The reaction mixture was cooled to room temperature and stirred for 4 h at the same temperature. The obtained solid was filtered and dried producing 286 g (71%) of the product as a white solid. 1 H-NMR (300 MHz): d 8.1 (q,, 1 H), 7.5 (t,, 1 H), 7.4 (d,, 2 H), 7.1 (d,, 2 H) , 7.0 (d,, 1H), 2.2 (s, 3H).
Step 2: Preparation of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine A solution with stirring of PTSA salt in ethyl acetate or dichloromethane to pH 12 was basified using aqueous sodium hydroxide solution. The final treatment and isolation of the product gave the free thiazolamine as a white solid.
Method C: Alternatively, 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine can be prepared by the following described method in WO 2010/10933.
Intermediate product 2 Preparation of 6-Chloro-1,3-dimethylpyrimidin-2,4 (1 / - /, 3H) -dione: Method A: To an ice-cooled solution of 1,3-dimethylbarbituric acid (50.0 g, 320.22 mmol) in water (20 mL), phosphorus oxychloride (200 mL) was added dropwise and the The resulting mixture is refluxed for 3 h. The reaction mixture was cooled to 0 ° C. The reaction mixture was quenched with ice water (500 ml) and extracted with chloroform (2 × 500 mi). The combined organic extract was washed with water (2 x 200 ml), dried (Na 2 SO 4) and concentrated to obtain the desired product (yield: 90%); 1 H-NMR (300 MHz, CDCl 3): d 3.33 (s, 3 H), 3.57 (s, 3 H), 5.94 (S, 1 H). APCI-MS (m / z) 175.26 (M + H) +. IR (KBr): 3074.9, 2961.4, 1704, 1651, 1027, 755, 486 cm 1. Melting point: 111-114 ° C by DSC.
Method B: To an ice-cooled solution of 1,3-dimethylbarbituric acid (1 Kg) in water (300 ml), phosphorus oxychloride (3.3 I) was added dropwise and the mixture was refluxed. reaction for 3 h. After completion of the reaction, the excess phosphorus oxychloride was evaporated under reduced pressure. The reaction mixture was quenched using ice water with cooling. The mixture was extracted with dichloromethane (2 x 2.5 L). He washed the organic extract combined with saturated sodium bicarbonate solution (2.5 L), dried (anhydrous Na 2 SO 4) and concentrated to obtain the product. The product was washed with ethanol (0.5 L) and dried to obtain 0.9 Kg of the title compound.
Intermediate product 3 Preparation of 1,3-dimethyl-6-sulfanylpyrimidine-2,4 (1 / - /, 3 / - /) - dione Method A: A solution of hydrous sodium hydrosulfate (74.77 g, 1335.243 mmol) in water (125 ml) was added dropwise to a stirred solution of 6-chloro-1,3-dimethylpyrimidin-2, 4 (1 / - /, 3 / - /) -dione (50.0 g, 286.532 mmol) in a mixture of chloroform (250 ml) and ethanol (636 ml) at 0 ° C and the resulting mixture was stirred at room temperature Atmosphere during the night. The reaction mixture was evaporated to dryness in vacuo. The residue obtained was dissolved in water (100 ml) and extracted with dichloromethane (2 x 100 ml). The aqueous phase was acidified with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water (2 x 100 mL) and dried to obtain the desired product (yield: 98%); 1 H-NMR (300 MHz, CDCl 3): d 3.33 (s, 3 H), 3.74 (s, 3 H), 4.17 (s, 2 H); APCI-MS (m / z) 171, 33 (M-H)? IR (KBr): 3093, 2946, 1729, 1681, 1062, 1034, 754 cm 1. Melting point: 130-134 ° C (DSC).
Method B: To a stirring solution of 6-chloro-1,3-d.methylpyrimidin-2,4 (1H, 3H) -dione (550.0 g, 3.16 mol) in absolute ethanol (5, 5 I) was added sodium hydrate hydrate (550.0 g 9.8 mol) in portions at 0-5 ° C over a period of 45 min. After completion of the addition, the reaction mixture was stirred at 25-30 ° C for 1 to 2 h. The reaction mixture was filtered and washed with absolute ethanol (1.1 I). The filtrate was concentrated in vacuo to obtain a residue which was then dissolved in water (2.75 I). The aqueous solution was washed with dichloromethane (2 x 2.2 L) followed by petroleum ether (1.1 L). The aqueous solution was acidified using hydrochloric acid (2.2 I) [equal portion of conc. Hydrochloric acid. and water (1: 1)]. The precipitated solid was filtered and washed with water and dried to obtain the desired product (yield: 440 g, 86.2%).
Method C: To the solution with stirring solution of 6-chloro-1,3-dimethylpyrimidin-2,4 (1 / - /, 3 / - /) - dione (1 Kg) in ethanol (12 I) was added sodium hydrate hydrate (1 kg) in portions over a period of 1 h at 0 to 5 ° C. After the addition, the reaction mixture was stirred at 25 to 30 ° C for 2 h. The reaction mixture was filtered and washed with ethanol (2 L). The filtrate was collected and concentrated in vacuo to obtain a residue which was then dissolved in water (8 1). The aqueous solution was washed with dichloromethane (3 I) followed by petroleum ether (2 I). The aqueous phase was separated and acidified using hydrochloric acid solution [4 I, conc. Hydrochloric acid. and water (1: 1)]. The precipitated solid was filtered and washed with water followed by ethanol and dried to obtain 0.8 kg of the title compound.
Intermediate product 4 Preparation of Ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate Method A: To a stirring solution of 1,3-dimethyl-6-sulfanylpyrimidin-2, 4 (1 / - /, 3H) -dione (49 g, 284.883 mmol) in dry dichloromethane (60 mL) was added triethylamine (43.23 g, 427.325 mmol) and ethyl 4-chloroacetoacetate (56.26 g). , 341, 860 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (800 ml) and extracted with chloroform (2 x 750 ml). The combined organic phase was washed with water (500 ml), dried over Na 2 SO 4 and evaporated to give a product, which was crystallized from methanol (180 ml) and hexane (360 ml) obtaining a product as a white solid (yield: 50 %); 1 H-NMR (300 MHz, CDCl 3): d 1.31 (t, J = 7.5 Hz, 3H), 3.32 (s, 3H), 3.53 (S, 3H), 3.65 (s) , 2H), 4.06 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 5.46 (s, 1H); APCI-MS (m / z) 301.03 (M + H) +. IR (KBr): 2975, 1736, 1703, 1645, 1449, 1325, 1192, 1021 cm \ Melting point: 118-122 ° C (DSC).
Method B: The mixture of 1,3-dimethyl-6-sulfanylpyrimidin-2,4 (1 H, 3 / - /) -dione (837 g, 0.011 mol) and 4-chloroethyl acetoacetate (1315 ml, 0.022) was stirred. mol) in ethanol (6.6 I) at 25 to 30 ° C for 36 h. The obtained solid was filtered and washed with ethanol (418 ml) yielding a product as an off-white solid (yield: 962 g, 66%).
Method C: The mixture of 1,3-dimethyl-6-sulfanylpyrimidin-2,4 (1 / - /, 3H) -dione (1 Kg) and 4-chloroethyl acetoacetate (1.58 I) in ethanol was stirred ( 6.6 I) at 25 to 30 ° C for 36-40 h. The product obtained was filtered and washed with ethanol (0.5 L) followed by petroleum ether (1 L) to obtain 1 kg of the title compound as an off-white solid.
Intermediate product 5 Preparation of ethyl (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetate: Method A: A mixture of ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyridin-4-yl) sulfanyl] -3-oxobutanoate was stirred. (450 g) and polyphosphoric acid (4 Kg) at 60-70 ° C for 2 h. The reaction mixture was cooled to room temperature and quenched carefully with water (24 I). The mixture was extracted with ethyl acetate (2 x 2.25 L) and the combined organic phase was washed with water (2 x 2.25 L). The mixture was dried over sodium sulfate Sodium and concentrated obtaining a residue which was triturated with ethanol (450 ml) to give a product as an off-white solid (yield: 340 g, 80%). 1 H-NMR (300 MHz, CDCl 3): d 1.26-1.31 (t, 3H), 3.39 (s, 3H), 3.55 (s, 3H), 3.93 (s, 2H) , 4.16-4.23 (q, 2H), 6.70 (s, 1H), APCI-MS (m / z) 283.0 (M + H) +. IR (KBr): 3114, 2986, 1722, 1697, 1657, 1495, 1201 cm 1.
Melting point: 159-160 ° C (DSC).
Method B: To a stirred solution of ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate (42, 10 g, 140.802 mmol) in dry toluene (420 mL) was added phosphorus pentoxide (29.97 g, 211, 204 mmol) and the reaction mixture was heated at reflux temperature for 2 h. The reaction mixture was cooled to room temperature and quenched with water (400 ml). The mixture was extracted with ethyl acetate (2 x 400 mL) and the combined organic phase was washed with water (200 mL). The organic phase was dried (Na2SO) and concentrated. The residue obtained after evaporation of the solvent was crystallized from methanol to give the product as an off-white solid (yield: 68%).
Method C: To a stirred solution of ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate (300 mg , 1.00 mmol) in dry toluene (10 mL) was added anhydrous zinc chloride (163 mg, 1.20 mmol) and the reaction mixture was heated to reflux for 2 h. The solvent was evaporated under reduced pressure and diluted with water (25 ml). HE collected the precipitated solid by filtration, washed with water and dried to give the desired product as an off-white solid (yield: 78%).
Method D: To a stirred solution of ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate (200 mg , 0.666 mmol) in dry toluene (5 mL) was added a drop of concentrated sulfuric acid at room temperature and the resulting mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue obtained was diluted with water (25 ml). The precipitated solid was filtered, washed with water and dried to obtain the desired product as an off-white solid (yield: 33%).
Method E: A mixture of ethyl 2-bromo-4- (2-ethoxy-2-oxoethyl) thiophene-3-carboxylate (1.5 g, 0.0046 mol, intermediate 10) was refluxed, h / , L / '- dimethylurea (0.48 g, 0.0055 mol), Pd2 (dba) 3 (0.2 g, 4.2 mol%), Xantphos (4,5-bis (diphenylphosphino) -9.9 -d -methylxanthene) (0.2 g, 6.5 mol%) and Cs2CO3 (4.0 g, 0.012 mol in dioxane (15 mL) for 4 to 5 h. The reaction mixture was concentrated in vacuo and concentrated in vacuo. purified by column chromatography (20% ethyl acetate in hexane) to obtain the title compound as an off-white solid (0.4 g, 30%). 1 H-NMR (300MHz, CDCl 3): d 1.26-1, 31 (t, 3H), 3.39 (s, 3H), 3.55 (s, 3H), 3.93 (s, 2H), 4.16-4.23 (q, 2H), 6.71 (s, 1 H), APCI-MS (m / z) 283.0 (M + H) +. IR (KBr): 3114, 2986, 1722, 1697, 1657, 1495, 1201 cm 1. Melting point: 159-161 ° C.
Method F: A mixture of ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate (1 kg) was stirred. and polyphosphoric acid (8 kg) at 60-70 ° C for 2 h. The reaction mixture was cooled to room temperature and carefully quenched with water (40 I). The precipitated solid was filtered and washed with water (2 I). The precipitate was dissolved in dichloromethane (10 L), and the mixture was washed with water (2 x 3 L). The phases were separated, the organic phase was dried over anhydrous sodium sulfate and treated with charcoal (10 g) and filtered. The filtrate was concentrated to give a residue which was triturated with ethanol (0.5 L) to give 0.7 kg of the title compound.
Intermediate product 6 Preparation of acid (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydric acid [2,3-c (] pyrimidin-5-yl) acetic acid Method A: A mixture of (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-] pyrimidin-5-yl) acetate was heated to reflux. ethyl (1.3 g, 4.850 mmol) and H2SO4 (6 N, 12 mL) in 1,4-dioxane (12 mL) for 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with water (50 ml), separated, dried over sodium sulfate. anhydrous sodium and concentrated under reduced pressure. The residue obtained was triturated with diethyl ether. The solid was filtered and washed with diethyl ether (10 mL) to obtain 450 mg of product (yield: 40%); 1 H-NMR (300 MHz, DMSO-de): d 3.21 (s, 3 H), 3.45 (s, 3 H), 3.79 (s, 2 H), 7.01 (s, 1 H), 12 , 22 (sa, 1 H).
Method B: A solution of ethyl (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (l-pyrimidin-5-yl) acetate (340.0) was stirred. g, 1.20 mol) in 1,4-dioxane (1700 ml) for 30 min at room temperature, followed by the addition of sulfuric acid (3 N, 133 ml in 1700 ml of water). of reaction for 3 to 4 h and concentrated in vacuo to obtain an oily mass, diluted with water (1700 ml) and stirred for 30 min at 25 to 30 ° C, obtaining the product as a light brown solid which was The product was dried well and further stirred in dichloromethane (1220 ml), the solid was filtered, washed with dichloromethane (680 ml) and dried to yield the title compound (yield: 244 g, 80%). ).
Method C: A solution of (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) ethyl acetate (1 kg) in 1,4-dioxane (5 I) for 30 min at room temperature, followed by the addition of sulfuric acid (3 N, 0.4 I in 5 l of water). The reaction mixture was heated to 80- 90 ° C for 3 to 4 h. To the reaction mixture, water (10 I) was added and it was cooled to 25-30 ° C. The crude solid product was filtered and washed with water (2 x 1 L). The product was dried well and further stirred in dichloromethane (4 L). The solid was filtered, washed with dichloromethane (1 L) and dried to provide 0.6 kg of the title compound.
Intermediate product 7 Preparation of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) thio] -3-oxobutanamide To a stirring solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazoI-2-amine (224 mg, 0.801 mmol) in dry toluene (6 mL) was added hydride of sodium (60% dispersion in mineral oil, 48 mg, 1.214 mmol) and the reaction mixture was stirred at room temperature for 30 min. Ethyl 4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) sulfanyl] -3-oxobutanoate (200 mg, 0.607 mmol) was added to the mixture of the above reaction, and the resulting mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine and dried over Na2SO4. The filtrate was concentrated under reduced pressure. The crude residue thus obtained was purified by silica gel column chromatography using 2% methanol in chloroform obtaining the product as a white solid (yield: 25%); 1 H-NMR (300 MHz, CDCl 3): d 3,14 (s, 3H), 3.41 (s, 3H), 3.95 (s, 2H), 4.43 (s, 2H), 5.60 (s, 1H), 7.53 (t, J = 9.0 Hz, 1H ), 7.67 (s, 1 H), 8.25-8.35 (m, 1 H), 12.51 (s at, 1 H).
Intermediate product 8 Preparation of 5- [2- (1 / - / - Benzotriazol-1-yl) -2-oxoethyl] -1,3-dimethylthieno [2,3-c] pyrimidine-2,4 (1 / - /, 3 / - /) - diona: To a stirring solution of benzotriazole (563 mg, 4.724 mmol) in dry dichloromethane (15 mL) was added thionyl chloride (140 mg, 92 mL, 1.181 mmol) and the reaction mixture was stirred at room temperature for 30 min. . To the reaction mixture was added (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothione [2,3-c] pyrimidin-5-yl) acetic acid (300 mg, 1.181 mmol) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed by distillation under reduced pressure. The residue obtained was purified after evaporation of the solvent by silica gel column chromatography using 10% ethyl acetate in chloroform to obtain 520 mg of the product as an off-white solid; 1 H-NMR (300 MHz, CDCl 3): d 3.33 (s, 3 H), 3.59 (s, 3 H), 5.04 (s, 2 H), 6.84 (s, 1 H), 7, 52 (t, J = 7.8 Hz, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8, 24 (d, J = 8.1 Hz, 1H).
Intermediate product 9 Preparation of 2-amino-4-ethoxycarbonylmethyl-thiophene-3-carboxylic acid ethyl ester: To a stirred solution of ethyl 4-bromoacetoacetate (275 g, 1.31 mol), ethyl cyanoacetate (150 ml, 1.33 mol) in ethanol (3.5 L) was added Na 2 S 9 H 2 O (330 g). , 4.23 mol) followed by the dropwise addition of triethylamine (210 ml, 1.5 mmol) and the resulting mixture was stirred at 40-45 ° C for 36 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated, dried over Na2SO4 and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (n-hexane: ethyl acetate 4: 1) to give the title compound. (36 g, 12%). 1 H-NMR (300MHz, CDCl 3): d 1.27 (m, 6H), 3.68 (s, 2H), 4.19 (m, 4H), 6.00 (s, 1H), 6.18 ( a, 2H); APCI-MS (m / z) 257.96 (M + H) +. IR (KBr): 3415.8, 3315.7, 2981, 1733, 1657, 1604, 1489, 1479, 1272, 1174, 1071, 1028, 707.8 cm 1. Melting point: 71 ° C.
Intermediate product 10 Preparation of 2-bromo-4- (2-ethoxy-2-oxoethyl) thiophene-3-carboxylate from ethyl: Anhydrous copper (II) bromide (7 g, 0.031 mol) and tere-butyl nitrite (6 g, 0.058 mol) in acetonitrile were added to a solution of 2-amino-4-ethoxycarbonylmethyl-thiophene-3-ethyl ester. carboxylic acid (10 g, 0.038 mol) in acetonitrile at 25 to 30 ° C and the resulting mixture was stirred at 60-65 ° C for 1 to 2 h. After completion of gas evolution, the reaction mixture was allowed to cool to room temperature and poured into 10% aqueous hydrochloric acid solution. The reaction mixture was extracted with diethyl ether. The ether phase was concentrated and purified by column chromatography (25% ethyl acetate in hexane) to give the desired product as an oil (3.1 g, 24%). 1 H-NMR (300MHz, DMSOd 6): d 1.15-1, 19 (t, 3H), 1.26-1.30 (t, 3H), 3.84 (s, 2H), 4.04-4 , 10 (q, 2H), 4.18-4.25 (q, 2H), 7.50 (s, 1H), APCI-MS (m / z) 322.90 (M + H) +. KBr): 3434, 2927, 1643, 1537, 1028, 747 cm 1 Example 1 Preparation of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide: Method A: A solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (38.66 g, 0.138 mol) in dichloromethane (154 ml) was added to a solution of 1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] p-idmidin-5-yl) acetic acid (29.0 g, 0.114) mol) in dichloromethane (174 ml) at 0 ° C and the resulting mixture was stirred for 5 min. To the above mixture was added 1-hydroxybenzotriazole (HOBt) (5, 80 g, 0.0429 mol) followed by / V-methylmorpholine (13.53 g, 0.133 mol) and the reaction mixture was stirred for 30 min. To it (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (25.90 g, 0.135 mol) was added and the reaction mixture was stirred at 0 ° C for 3 h. The reaction mixture was allowed to warm to 25 to 30 ° C and was stirred for 22 to 24 h. The precipitated solid was filtered and washed with dichloromethane. It was further purified by dissolving in DMSO (1000 ml) at 60 to 65 ° C and filtered through a pad of Celite. To the filtered solution, demineralized water (3.5 L) was added. The resulting precipitated product was filtered on a Buchner funnel at 25 to 30 ° C and washed with water. The solid was discharged and dried (yield: 47 g, 65%). 1 H-NMR (300 MHz, DMSO efe): d 3.19 (s, 3 H), 3.46 (s, 3 H), 4.07 (s, 2 H), 7.07 (s, 1 H), 7, 48-7.54 (t, J = 9.0 Hz, 1H), 7.61 (s, 1H), 8.30-8.37 (q, J = 7.8 Hz, 1H), 12.48 (sa, 1 H); ESI-EM. { m / z): 517.09 (M + H) +. IR (KBr): 3218, 3101, 1699, 1642, 1626, 1561, 1480, 1307, 1128, 1019, 743 cm 1. Melting point: 274 ° C.
Method B: To a stirring solution of 4- [2,4-difluoro-3-] (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (11.9 g, 42.553 mmol) in dry toluene (350 mL) was added sodium hydride (60% dispersion in mineral oil, 1, 02 g, 42.553 mmol) and the reaction mixture was stirred for 30 min at room temperature. (Ethyl 1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetate (10.0 g, 35.460 mmol) was added. to the above reaction mixture and refluxed for 24 h.The reaction mixture was cooled to room temperature and another portion of sodium hydride (60% dispersion in mineral oil, (1.02 g, 42.553 mmol) was added. ) and refluxed further for 24 h.The solvent was evaporated under reduced pressure and quenched using HCl (1 N, 150 ml) The precipitated solid was collected by filtration and recrystallized from isopropyl alcohol to give the product as a solid white (yield: 90%).
Method C: To a solution with agitation of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -4 - [(1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropyrimidin-4-yl) thio] -3-oxo-butanamide (85 mg, 0.159 mmol) in dry toluene ( 1.5 ml) was added phosphorus pentoxide (34 mg, 0.238 mmol) at room temperature and the resulting mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature and quenched with water (15 ml). The mixture was extracted with ethyl acetate (2 x 15 mL) and the organic extract was washed with water (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue obtained was purified after evaporation of the solvent by chromatography on silica gel column using 10% ethyl acetate in chloroform to give the product as an off-white solid (yield: 65%); Method D: To a stirring solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (118 mg, 0.422 mmol) in dry THF (15 mL), Sodium hydride (60% dispersion in mineral oil, (12.17 mg, 0.507 mmol) was added and the reaction mixture was stirred for 30 min at room temperature, 5- [2- (1H-benzothiazole- 1-yl) -2-oxoethyl] -1,3-dimethylthieno [2,3-c /] pimidin-2,4 (1 / - /, 3 / - /) -dione (150 mg, 0.422 mmol) at The reaction mixture was refluxed for 24 h.The solvent was removed under reduced pressure and quenched with HCl (1 N, 10 ml) The precipitated solid was collected by filtration, The solid was recrystallized from isopropyl alcohol to give the product as a white solid (yield: 15%).
Method E: To a stirred solution of (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetic acid (100 mg , 0.393 mmol) in 1,2-dichloroethane (4 mL) was added EDCI (90 mg, 0.471 mmol), HOBt (16 mg, 0.117 mmol) and 4-dimethylaminopyridine (5 mg, 0.039 mmol). The mixture was then stirred at room temperature for 10-15 min. Then 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (110 mg, 0.393 mmol) was added to the reaction mixture and stirred at room temperature for 48 hours. h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with methanol (15 ml). The mixture was stirred at room temperature for 30 min. The solid precipitate was collected by filtration. It was purified additionally the solid product by recrystallization from isopropanol to give the desired product.
Method F: To a stirred solution of acid (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c / | pyrimidin-5-yl) acetic acid (1 kg) in dichloromethane (6 I), was added 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine solution (1.33 kg) in dichloromethane (4 I) at 0-5 ° C and the mixture was stirred for 5 min. To the reaction mixture were added HOBt (0.2 kg) and A / -methylmorpholine (0.46 kg) and the reaction mixture was stirred for 30 min. To the reaction mixture was added (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (EDCI.HCl) (0)., 89 kg) and the reaction mixture was stirred for 3 h at 0-5 ° C. The reaction mixture was allowed to warm to 25 to 30 ° C and was stirred for 36-40 h. The precipitated solid was filtered and washed with dichloromethane. To the crude solid, DMSO (29 I) was added and stirred at 50 to 60 ° C until a clear solution was observed. The solution was filtered through a pad of Celite and to the filtrate, water (75 I) was added. The precipitated product was filtered, washed with water and dried to obtain 1.0 kg of the title compound.
Example 2 Preparation of form X of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide: .
To a stirred solution of (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid (0.5 g, 1 , 9 mmol) in 1,2-dichloroethane (20 mL) was added EDCI (0.43 g, 2.2 mmol), HOBt (0.07 g, 0.5 mmol) and 4-dimethylaminopyridine (0.02 g). g, 0.1 mmol). The reaction mixture was stirred at room temperature for 10-15 min. 4- [2,4-Difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (0.55 g, 1.9 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with methanol (20 ml). The reaction mixture was stirred at room temperature for 30 min. The separated solid was collected by filtration. It was washed with methanol and dried to obtain 0.240 g of the X form of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide.
Example 3 Preparation of the Y form of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide: To a solution of (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid (300 g, 1.181 mol) in dichloromethane (1.8 I), a solution of 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-amine (400.5 g) was added at 0-5 ° C. , 1, 430 mol) in dichloromethane (1.2 I). The reaction mixture was stirred for 5 min. To the reaction mixture were added HOBt (60 gm, 0.44 mol) and A / -methylmorpholine (139.94 g, 1.36 mol) and the reaction mixture was stirred for 30 min. To the reaction mixture, (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (EDCI.HCI) hydrochloride (267.91 gm, 1.39 mol) was added and stirred for 3 h at 0-5 °. C. The reaction mixture was allowed to warm to 25 to 30 ° C and was stirred for 36-40 h. The precipitated solid was filtered and washed with dichloromethane. The obtained solid was dried obtaining 385 g of the Y form of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide.
Example 4 Preparation of the Z form of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c pyrimidin-5-yl] acetamide: A solid obtained in Example 2 was dissolved in DMSO (7.3 I) and stirred at 50 to 60 ° C to obtain a clear solution. Charcoal (3.6 g) was added to the solution and stirred. The solution was filtered through a pad of Celite. To the filtrate, water (15 L) was added and stirred. The precipitated solid was filtered, washed with water and dried to obtain 365 g of the Z form of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3- dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide.
Example 5 Preparation of the crystalline potassium salt of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (l-pyrimidin-5-yl) acetamide] designated form I.
To a solution with stirring of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide (1.0 g, 1.93 mmol ) in absolute ethanol (7.0 ml) and n-pentane (25 ml) was added dropwise freshly prepared potassium tert-butoxide in ethanol (0.228 g of potassium tert-butoxide in 3.0 ml of ethanol) under a nitrogen atmosphere at -5.0 to 0 ° C and the resulting mixture was stirred at the same temperature for 1.0 h. N-Pentane (5.0 ml) was added and the reaction mixture was kept for 1-2 h at room temperature. The solid obtained was filtered and dried for 3 to 4 h at 30 to 35 ° C under vacuum. The dried solid was stirred in acetonitrile (10 ml) for 1 to 2 h. The solid was collected in a Buchner funnel and washed with acetonitrile (2 ml). The solid was dried for 8 to 10 h at 30 to 35 ° C under vacuum. 1 H-NMR (300 Hz, DMSO-cfe): 8.373-8.452 (m, 1H); 7.338-7.403 (t, 1H); 7.037-7.048 (d, J = 3.3, 1H); 6.903 (s, 1 H); 3,827 (s, 2H); 3,465 (s, 3H); 3,235 (s, 3H). APCI-MS (m / z)? 517.02 (M + H) +. Yield: 89.89%.
Example 6 Preparation of the crystalline potassium salt of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pinmidin-5-yl) acetamide] designated form II.
To a solution with agitation of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c] pyrimidin-5-yl) acetamide crystalline (1.0 g (1, 93 mmol) in n-pentane (25.0 ml) was added f-butanol (6.0 ml) at -5.0 at 0 ° C under nitrogen atmosphere and the resulting mixture was stirred for 10 min. this reaction mixture was added dropwise freshly prepared solution of potassium t-butoxide in f-butanol (0.239 g of potassium f-butoxide in 2.0 ml of f-butanol) at -5 to 0 ° C and it was stirred at the same temperature for 1 h The obtained solid was filtered and washed with 5.0 ml of n-pentane The solid was dried for 3-4 h at 30-35 ° C under vacuum The dried solid was charged In a flask followed by the addition of 10 ml of acetonitrile, the reaction mixture was stirred for 1-2 h, the solid was filtered and washed with 1.0 ml of acetonitrile and dried for 8-10 h at 30-35. ° C to vacuum Yield: 0.9 g, 90%.
Example 7 Preparation of amorphous potassium salt of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamidate] The potassium salt of A / - was heated to 300-320 ° C. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide (1 g) on a blanket heating to melt the compound under reduced pressure. It was then cooled to room temperature to obtain 0.8 g of the amorphous form.
Example 8 Preparation of the crystalline sodium salt of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide] designated form A.
He took / \ / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide (1.0 g 1.93 mmol) to a flask followed by the addition of absolute ethanol (15.0 ml) under nitrogen atmosphere. The reaction mass was cooled to -5.0 to 0 ° C and was further maintained for 10 min. In an independent flask, sodium methoxide solution was prepared at -3.0% in ethanol (0.157 g of sodium methoxide in 5.0 ml of ethanol). The sodium methoxide solution was slowly added to the reaction mass at -5 to 0 ° C and held for 1 h. The solvent was removed by distillation at 30 to 35 ° C to obtain a solid. The solid was dried for 1 to 2 h at 30-35 ° C under vacuum. The dried solid was stirred in acetonitrile (10 ml) for 1-2 h at room temperature. The solid was collected in a Buchner funnel and dried for 3 to 4 h at 30 to 35 ° C under vacuum. 1 H-NMR (300 Hz, D SO-d 6): 8.382 (m, 1 H); 7,458-7,393 (t, 1 H); 7.273-7.263 (d, J = 3.0, 1 H); 6.96 (s, 1 H); 3.937 (s, 2H); 3.461 (s, 3H); 3,214 (s, 3H). APCI-MS (m / z): 517.02 (M + H) +.
Yield: 86.37%.
Example 9 Preparation of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidn-5-yl) acetamide] sodium in amorphous form It took / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-cf] pyrimidin-5-yl) acetannide (1 g 1.93 mmol) at a flask followed by the addition of absolute ethanol (20 ml) under a nitrogen atmosphere. The reaction mixture was cooled to -5 to 0 ° C and further maintained for 10 min. In an independent flask, sodium tert-butoxide solution was prepared at ~ 4% in ethanol (0.195 g of sodium tert-butoxide in 5 ml of ethanol). The sodium tert-butoxide solution was added slowly in the reaction mass at -5 to 0 ° C and maintained for 1 h. The solvent was removed by distillation completely at 30 to 35 ° C under vacuum until a solid was obtained. The solid was dried for 1 to 2 h at 30 to 35 ° C in vacuo. 1 H-NMR (300 Hz, DMSO-d 6): 8.37-8.45 (m, 1H); 7.37-7.43 (t, 1H); 7.09-7.08 (d, J = 3.0 Hz, 1H); 6.90 (s, 1 H); 3.83 (s, 2H); 3.46 (s, 3H); 3.23 (s, 3H). APCI-MS (m / z): 517.02 (M + H) +. Yield: 91.40%.
Example 10 Preparation of the crystalline lithium salt of [A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-] pyrimidin-5-yl) acetamide] designated alpha.
He took A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (jpyrimidin-5-yl) acetamide (1 g; 93 mmol) was added to a flask followed by the addition of absolute ethanol (20 ml) under a nitrogen atmosphere, the reaction mixture was cooled to -5 to 0 ° C and maintained for 10 min, lithium hydroxide was slowly added. monohydrate (0.122 g, 2.90 mmol) in portions to the reaction mixture at -5 to 0 ° C and was further maintained for 1 h.The solvent was removed by distillation completely at 30 to 35 ° C under vacuum obtaining A solid The solid was dried for 1 to 2 h at 30-35 ° C in vacuo The solid was stirred in diethyl ether (15 ml) for 1 to 2 h, collected in a Buchner funnel and washed with diethyl ether. ether (15 mL) The solid was dried for 1 to 2 h at 30 to 35 ° C under vacuum, 1 H-NMR (300 Hz, DMSO-c / 6): 8.42-8.36 (m, 1 H). ), 7.36-7.43 (t, 1H), 7.03-7.04 (d, J = 3.3 Hz, 1H), 6.89 (s, 1 HOUR); 3.81 (S, 2H); 3.42 (s, 3H); 3.23 (s, 3H). APCI-MS (m / z): 517.02 (M + H) +. Performance: 90%.
Example 11 Solubility studies of the compound of formula (II) and its sodium and potassium salts l. Methodology: The oscillating flask method was used to determine the solubility of the compound in various biologically relevant media of different pH and quantification is performed using an HPLC method.
II. Experimental part: The following relevant media were selected biologically and water to study the solubility behavior. i. FaSSIF (simulated intestinal fluid in fasting state) of pH 6.5 ii. FeSSIF (simulated intestinal fluid in the fed state) of pH 5.0 .Water.
Procedure: the test substance (1 mg) was taken to a test tube and the medium [FaSSIF (pH 6.5) or FeSSIF (pH 5.0) or water] was added in 1 ml increments with stirring. After the addition of 10 ml of media was complete, the test sample containing tubes were placed in a mechanical stirrer set at 37 ° C and 200 rpm to stir until about 15 minutes. After stirring, the contents of each flask were filtered through a 0.45 m filter. The filtered solution was analyzed using HPLC for quantification. A 1 mg sample solution in 10 ml of DMSO was used as a reference standard to quantify the test substance dissolved in each medium. The solubility in each medium is expressed as mg / ml (table 10).
Table 10: Solubility data for compound (II) and its sodium and potassium salts Example 12 Stability studies of salts of the compound of formula II: The salts of the compound of formula II were stored under conditions as shown in the following table and was estimated by HPLC the total amount of degradation products (related substances) as well as the maximum individual impurity formed during storage. The material was packed in internal transparent polyethene bag under nitrogen coated with black polyethylene bag, covered with triple laminated aluminum bag, placed in HDPE drum and subjected to the conditions mentioned in table 11.
Table 11: Stability of salts of the compound of formula II in storage condition 1: Table 12: Stability of salts of the compound of formula II in storage condition 2: Table 13: NT: not tested Stability of salts of the compound of formula II in storage condition n 3: Table 14: Example 13 Dissolution studies of the compound of formula (II), the sodium salt of the compound of formula (II) and the potassium salt of the compound of formula (II): A suspension of the compound of formula (II) and its salts with the same composition was prepared using conventional homogenization technique. The% drug release was determined by comparing with an equivalent suspension of 10 mg (after sonication).
Table 15: Dissolution studies of the compound of formula (II), its sodium salt and its potassium salt as a suspension

Claims (28)

1. Potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-tiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide represented by the formula (II)
2. Potassium salt of / V-. { 4- [2,4-D-fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothione [2,3-c (! Pyrimidin-5-yl) acetamide represented by the formula (II ) in crystalline form.
3. V- crystalline potassium salt. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide designated form I characterized by the diffraction pattern of X-ray powder (XRPD) provided in figure 1.
4. A / - crystalline potassium salt. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4- tetrahydrothieno [2,3- / lp¡rinn¡din-5-yl) acetamide designated form I characterized by the powder X-ray diffraction pattern (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 15.93, 20.61, 23.63, 24.47 and 25.08 ± 0.2.
5. A / - crystalline potassium salt. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-cdpyrimidin-5-yl] acetamide designated form I characterized by the X-ray diffraction pattern of powder (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 23.63 and 24.47 ± 0.2.
6. A / - crystalline potassium salt. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide designated form II which is characterized by the standard Diffraction X-ray powder (XRPD) provided in Figure 3.
7. A / - crystalline potassium salt. { 4- [2,4-d.fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) acetamide designated form II characterized by the diffraction pattern of X-ray powder (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 12.07, 12.39, 20.98, 24.01 and 25.69 ± 0.2.
8. C / V- potassium salt. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrinnidin-5-yl) acetamide designated form II characterized by the diffraction pattern of X-ray powder (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 24.01 and 25.69 ± 0.2.
9. Amorphous form of the potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide.
10. Amorphous form of the potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-l, 2,3,4-tetrahydrothieno [2,3-cdpyrimidin-5-yl] acetamide) characterized by powder X-ray diffraction pattern (XRPD) provided in figure 5.
11. Potassium salt of / V- (4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl.} -2- (1,3-dimethyl-2,4) -dixo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide according to claim 1, which has a water content of less than about 5%.
12. Potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidn-5-yl) acetamide according to claim 1, in the one that 10% of the particles (D-io) have a size in the range of from about 0.3 mlti up to about 10 m? ti.
13. Potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c | pyrimidin-5-yl] acetamide according to claim 1, wherein the 10% of the particles (D10) have a size in the range of 0.5 mhh to about 5 mhi.
14. Potassium salt of A / - (4- [2,4-difluoro-3- (tnfluoromethyl) phenyl] -1,3-tiazol-2-yl.} -2- (1,3-d) Methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c (! Pyrimidin-5-yl) acetamide according to claim 1, wherein 90% of the particles (D90) they have a size in the range of from about 4 m? ti to about 300 mhh.
15. Potassium salt of A / - [4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide according to claim 1, wherein 90% of the particles (Dgo) have a size in the range of from about 5 pm to about 150 mhh.
16. Potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide according to the claim, which has a size of average particle (D50) in the range of from about 1 pm to about 100.
17. Potassium salt of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1, 3- thiazol-2-il} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3- / | pyrimidin-5-yl) acetamide according to claim 1, which has a size of average particle (D50) in the range of from about 1 mhh to about 20 mhi.
18. Procedure for the preparation of the crystalline potassium salt of / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) acetamide designated form I, process comprising the following steps : (a) carry A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (! Pyrimidin-5-yl) acetamide to a mixture of ethanol and n-pentane; (b) adding ethanolic solution of potassium tert-butoxide or potassium ethoxide to the solution or suspension of step (a) or adding the solution or suspension of step (a) to ethanolic solution of potassium tert-butoxide or ethoxide of potassium: and (c) isolate the desired salt of potassium.
19. Process for the preparation of the crystalline potassium salt of A / - [4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide designated form II, which process comprises The following stages: (a) carry A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c / | pyrimidin-5-yl) acetannide to a mixture of tert-butanol and n-pentane; (b) adding potassium tert-butoxide in tert-butanol to the solution or suspension of step (a) or adding the solution or suspension of step (a) to potassium tert-butoxide in tert-butanol; Y (c) isolate the desired salt of potassium.
20. / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) crystalline acetamide designated form Y characterized by the diffraction pattern of X-ray powder (XRPD) provided in figure 14.
21. / \ / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c /] pyrimidin-5-yl) crystalline acetamide designated form Y characterized by the diffraction pattern X-ray powder (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 4.72, 9.40, 21, 04, 25.87 and 31, 73 ± 0.2.
22. / V- [4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-cf] pyrimidin-5-yl) crystalline acetamide designated form Y characterized by the infrared spectroscopy pattern by Fourier transform (FT-IR) in which the ratio between the intensity of the absorption bands at wavelengths of 1500 cm 1 and 1480 cm 1 is from 1: 1, 7 to 1: 2.4.
23. TO-. { 4- [2,4-Clifluoro-3- (trifluoromethyl) phenyl] -1,3-t-azozol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) crystalline acetamide designated Z-form characterized by the diffraction pattern X-ray powder (XRPD) provided in figure 16.
24. TO/-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c (] pyrimidin-5-yl) crystalline acetamide designated form Z characterized by the powder X-ray diffraction pattern (XRPD) comprising one or more of the following peaks expressed in terms of 2Q: 10.63, 19.25, 22.11, 22.76 and 27.27 ± 0 ,2.
25. / V-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-c (pyrimidin-5-yl) acetamidade crystalline designated Z form characterized by the Fourier transform infrared spectroscopy pattern (FT-IR) in which the ratio between the intensity of the absorption bands at wavelengths of 1500 cm 1 and 1480 cm 1 is from 1: 2.5 to 1 : 2.9
26. Procedure for the preparation of A / -. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1, 3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-c / | pyrimidin-5-yl) acetamida or a pharmaceutically acceptable salt of the same, procedure comprising the stage of (a) treating dimethylbarbituric acid with a suitable chlorinating agent to provide 6-chloro-1,3-dimethyluracil of formula (1); Y (b) treating the 6-chloro-1,3-dimethyluracil of formula (1) with hydrous sodium sulfhydrate to give 6-mercapto-1,3-dimethyluracil of formula (2). (c) treating the 6-mercapto-1,3-dimethyluracil of formula (2) with the compound of formula (3) wherein R is alkyl , giving the ester compound of formula (4); Y C) (e) Cementing the ketoester of formula (4) to obtain the thieno-pyrimidinyl ester of formula (5)
27. TO/-. { 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazole-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydro] [2,3-c (] pyrimidin-5-yl) acetamide having less than about 0.1% (by HPLC) of the compound of formula (III):
28. Compound of formula (III) - or a pharmaceutically acceptable salt thereof.
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